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Fumiki Katsuoka

Section

Advanced Research Center for Innovations in Next-Generation Medicine

Job title

Professor

Degree

博士（医学）（筑波大学）
修士（医科学）（筑波大学）

researchmap

https://researchmap.jp/7000000389

J-GLOBAL ID

201201078180824963

Research History 11

2021/03 - Present

Tohoku University
2020/01 - Present

東北大学東北メディカル・メガバンク機構　ゲノム解析部門　教授
2012/05 - 2020/01

Tohoku University　Tohoku Medical Megabank Organization, Department of Integrative Genomics
2009/04 - 2012/04

Tohoku University　Graduate School of Medicine
2008/04 - 2009/03

Tohoku University　Graduate School of Medicine
2007/04 - 2008/03

University of Tsukuba
2006/12 - 2007/03

University of Tsukuba
2006/04 - 2006/11

科学技術振興機構　ERATO山本環境応答プロジェクト　博士研究員
2003/04 - 2006/03

日本学術振興会　特別研究員（PD）
2002/10 - 2003/04

日本学術振興会　未来開研究推進事業　博士研究員
2001/04 - 2002/09

ノースウエスタン大学　博士研究員

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Committee Memberships 1

日本生化学会　評議員

2020/09 - Present

Professional Memberships 2

THE MOLECULAR BIOLOGY SOCIETY OF JAPAN
THE JAPANESE BIOCHEMICAL SOCIETY

Research Interests 3

Oxidative Stress Response
genome analysis
transcriptional regulation

Research Areas 3

Life sciences / Molecular biology /
Life sciences / Pathobiochemistry /
Life sciences / Medical biochemistry /

Papers 109

Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals. International-journal

Yu-Ichi Aoki, Keiko Taguchi, Hayato Anzawa, Junko Kawashima, Noriko Ishida, Akihito Otuki, Atsushi Hasegawa, Liam Baird, Takafumi Suzuki, Ikuko N Motoike, Kinuko Ohneda, Kazuki Kumada, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

Journal of biochemistry　2024/01/24

DOI： 10.1093/jb/mvae008 　

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Whole blood transcriptome analysis is a valuable approach in medical research, primarily due to the ease of sample collection and the richness of the information obtained. Since the expression profile of individual genes in the analysis is influenced by medical traits and demographic attributes such as age and gender, there has been a growing demand for a comprehensive database for blood transcriptome analysis. Here, we performed whole blood RNA sequencing (RNA-seq) analysis on 576 participants stratified by age (20-30s and 60-70s) and gender from cohorts of the Tohoku Medical Megabank (TMM). A part of female segment included pregnant women. We did not exclude the globin gene family in our RNA-seq study, which enabled us to identify instances of hereditary persistence of fetal hemoglobin based on the HBG1 and HBG2 expression information. Comparing stratified populations allowed us to identify groups of genes associated with age-related changes and gender differences. We also found that the immune response status, particularly measured by neutrophil-to-lymphocyte ratio (NLR), strongly influences the diversity of individual gene expression profiles in whole blood transcriptome analysis. This stratification has resulted in a dataset that will be highly beneficial for future whole blood transcriptome analysis in the Japanese population.
jMorp: Japanese Multi-Omics Reference Panel update report 2023. International-journal

Shu Tadaka, Junko Kawashima, Eiji Hishinuma, Sakae Saito, Yasunobu Okamura, Akihito Otsuki, Kaname Kojima, Shohei Komaki, Yuichi Aoki, Takanari Kanno, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Jun Takayama, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Ritsuko Shimizu, Masahiro Hiratsuka, Ikuko N Motoike, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

Nucleic acids research　2023/11/01

DOI： 10.1093/nar/gkad978 　

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Modern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.
Construction of a trio-based structural variation panel utilizing activated T lymphocytes and long-read sequencing technology. International-journal Peer-reviewed

Akihito Otsuki, Yasunobu Okamura, Noriko Ishida, Shu Tadaka, Jun Takayama, Kazuki Kumada, Junko Kawashima, Keiko Taguchi, Naoko Minegishi, Shinichi Kuriyama, Gen Tamiya, Kengo Kinoshita, Fumiki Katsuoka, Masayuki Yamamoto

Communications biology　5　(1)　991-991　2022/09/20

DOI： 10.1038/s42003-022-03953-1 　

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Long-read sequencing technology enable better characterization of structural variants (SVs). To adapt the technology to population-scale analyses, one critical issue is to obtain sufficient amount of high-molecular-weight genomic DNA. Here, we propose utilizing activated T lymphocytes, which can be established efficiently in a biobank to stably supply high-grade genomic DNA sufficiently. We conducted nanopore sequencing of 333 individuals constituting 111 trios with high-coverage long-read sequencing data (depth 22.2x, N50 of 25.8 kb) and identified 74,201 SVs. Our trio-based analysis revealed that more than 95% of the SVs were concordant with Mendelian inheritance. We also identified SVs associated with clinical phenotypes, all of which appear to be stably transmitted from parents to offspring. Our data provide a catalog of SVs in the general Japanese population, and the applied approach using the activated T-lymphocyte resource will contribute to biobank-based human genetic studies focusing on SVs at the population scale.
Target Gene Diversity of the Nrf1-MafG Transcription Factor Revealed by a Tethered Heterodimer. International-journal Peer-reviewed

Fumiki Katsuoka, Akihito Otsuki, Nozomi Hatanaka, Haruna Okuyama, Masayuki Yamamoto

Molecular and cellular biology　42　(3)　e0052021　2022/03/17

DOI： 10.1128/mcb.00520-21 　

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Members of the cap'n'collar (CNC) family of transcription factors, including Nrf1 and Nrf2, heterodimerize with small Maf (sMaf) proteins (MafF, MafG, and MafK) and regulate target gene expression through CNC-sMaf-binding elements (CsMBEs). We recently developed a unique tethered dimer assessment system combined with small Maf triple-knockout fibroblasts, which enabled the characterization of specific CNC-sMaf heterodimer functions. In this study, we evaluated the molecular function of the tethered Nrf1-MafG (T-N1G) heterodimer. We found that T-N1G activates the expression of proteasome subunit genes, well-known Nrf1 target genes, and binds specifically to CsMBEs in the proximity of these genes. T-N1G was also found to activate genes involved in proteostasis-related pathways, including endoplasmic reticulum-associated degradation, chaperone, and ubiquitin-mediated degradation pathways, indicating that the Nrf1-MafG heterodimer regulates a wide range of proteostatic stress response genes. By taking advantage of this assessment system, we found that Nrf1 has the potential to activate canonical Nrf2 target cytoprotective genes when strongly induced. Our results also revealed that transposable SINE B2 repeats harbor CsMBEs with high frequency and contribute to the target gene diversity of CNC-sMaf transcription factors.
Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference. International-journal Peer-reviewed

Jun Takayama, Shu Tadaka, Kenji Yano, Fumiki Katsuoka, Chinatsu Gocho, Takamitsu Funayama, Satoshi Makino, Yasunobu Okamura, Atsuo Kikuchi, Sachiyo Sugimoto, Junko Kawashima, Akihito Otsuki, Mika Sakurai-Yageta, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Masayuki Yamamoto, Gen Tamiya

Nature communications　12　(1)　226-226　2021/01/11
Publisher: Cold Spring Harbor Laboratory
DOI： 10.1038/s41467-020-20146-8 　

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The complete human genome sequence is used as a reference for next-generation sequencing analyses. However, some ethnic ancestries are under-represented in the reference genome (e.g., GRCh37) due to its bias toward European and African ancestries. Here, we perform de novo assembly of three Japanese male genomes using > 100× Pacific Biosciences long reads and Bionano Genomics optical maps per sample. We integrate the genomes using the major allele for consensus and anchor the scaffolds using genetic and radiation hybrid maps to reconstruct each chromosome. The resulting genome sequence, JG1, is contiguous, accurate, and carries the Japanese major allele at most loci. We adopt JG1 as the reference for confirmatory exome re-analyses of seven rare-disease Japanese families and find that re-analysis using JG1 reduces total candidate variant calls versus GRCh37 while retaining disease-causing variants. These results suggest that integrating multiple genomes from a single population can aid genome analyses of that population.
Nrf2 contributes to the weight gain of mice during space travel. International-journal Peer-reviewed

Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

Communications biology　3　(1)　496-496　2020/09/08

DOI： 10.1038/s42003-020-01227-2 　

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Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining homeostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans.
Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells. International-journal Peer-reviewed

Fumiki Katsuoka, Akihito Otsuki, Mizue Takahashi, Shin Ito, Masayuki Yamamoto

Molecular and cellular biology　39　(20)　2019/10/15

DOI： 10.1128/MCB.00273-19 　

ISSN： 0270-7306

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A group of cytoprotective genes is regulated by heterodimers composed of the cap'n'collar (CNC) family member Nrf2 and one of the small Maf (sMaf) proteins (MafF, MafG, or MafK) through the antioxidant response element (ARE, also referred to as the CNC-sMaf binding element [CsMBE]). Many lines of evidence support this model; however, a direct and specific evaluation of the Nrf2-sMaf heterodimer remains to be executed. To address this issue, we constructed a tethered Nrf2-MafG (T-N2G) heterodimer using a flexible linker peptide. We then introduced the T-N2G construct into cells lacking all three sMaf proteins to specifically evaluate the function of the tethered heterodimer without interference from other endogenous CNC-sMaf heterodimers or sMaf homodimers. In response to an Nrf2 activator, diethyl maleate, the T-N2G protein can widely activate the target genes of Nrf2 but not those of Nrf1, such as proteasome subunit genes. Genome-wide binding analysis showed that the T-N2G protein preferentially bound to the CsMBE motifs in the regulatory regions of the Nrf2 target genes. These results provide direct evidence that the Nrf2-MafG heterodimer acts as a transcriptional activator of Nrf2-dependent genes and show that this assay system will be a powerful tool to specifically examine the function of other CNC-sMaf heterodimers.
Small Maf deficiency recapitulates the liver phenotypes of Nrf1- and Nrf2-deficient mice. International-journal Peer-reviewed

Fumiki Katsuoka, Hiromi Yamazaki, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　21　(12)　1309-1319　2016/12

DOI： 10.1111/gtc.12445 　

ISSN： 1356-9597

eISSN： 1365-2443
Small Maf proteins (MafF, MafG, MafK): History, structure and function. International-journal Peer-reviewed

Fumiki Katsuoka, Masayuki Yamamoto

Gene　586　(2)　197-205　2016/07/25

DOI： 10.1016/j.gene.2016.03.058 　

ISSN： 0378-1119

eISSN： 1879-0038
Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals. International-journal Peer-reviewed

Masao Nagasaki, Jun Yasuda, Fumiki Katsuoka, Naoki Nariai, Kaname Kojima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Junji Yokozawa, Inaho Danjoh, Sakae Saito, Yukuto Sato, Takahiro Mimori, Kaoru Tsuda, Rumiko Saito, Xiaoqing Pan, Satoshi Nishikawa, Shin Ito, Yoko Kuroki, Osamu Tanabe, Nobuo Fuse, Shinichi Kuriyama, Hideyasu Kiyomoto, Atsushi Hozawa, Naoko Minegishi, James Douglas Engel, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

Nature communications　6　8018-8018　2015/08/21

DOI： 10.1038/ncomms9018 　

ISSN： 2041-1723
NF-E2-related factor 1 (Nrf1) serves as a novel regulator of hepatic lipid metabolism through regulation of the Lipin1 and PGC-1β genes. International-journal Peer-reviewed

Yosuke Hirotsu, Nami Hataya, Fumiki Katsuoka, Masayuki Yamamoto

Molecular and cellular biology　32　(14)　2760-70　2012/07

DOI： 10.1128/MCB.06706-11 　

ISSN： 0270-7306
Mutations of CYP1B1 and FOXC1 genes for childhood glaucoma in Japanese individuals.

Nobuo Fuse, Masae Kimura, Ai Shimizu, Seizo Koshiba, Teruhiko Hamanaka, Makoto Nakamura, Nobuo Ishida, Hiroshi Sakai, Yoko Ikeda, Kazuhiko Mori, Atsushi Endo, Masao Nagasaki, Fumiki Katsuoka, Jun Yasuda, Yoichi Matsubara, Toru Nakazawa, Masayuki Yamamoto

Japanese journal of ophthalmology　2024/08/19

DOI： 10.1007/s10384-024-01103-0 　

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PURPOSE: To explore the frequency and positions of genetic mutations in CYP1B1 and FOXC1 in a Japanese population. STUDY DESIGN: Molecular genetic analysis. METHODS: Genomic DNA was extracted from 31 Japanese patients with childhood glaucoma (CG) from 29 families. We examined the CYP1B, FOXC1, and MYOC genes using Sanger sequencing and whole-exome sequencing (WES). RESULTS: For CYP1B1, we identified 9 families that harbored novel mutations, p.A202T, p.D274E, p.Q340*, and p.V420G; the remaining mutations had been previously reported. When mapped to the CYP1B1 protein structure, all mutations appeared to influence the enzymatic activity of CYP1B1 by provoking structural deformity. Five patients were homozygotes or compound heterozygotes, supporting the recessive inheritance of the CYP1B1 mutations in CG. In contrast, four patients were heterozygous for the CYP1B1 mutation, suggesting the presence of regulatory region mutations or strong modifiers. For the FOXC1 gene, we identified 3 novel mutations, p.Q23fs, p.Q70R, and p.E163*, all of which were identified in a heterozygous state. No mutation was found in the MYOC gene in these CG patients. All individuals with CYP1B1 and FOXC1 mutations were severely affected by early-onset CG. In the CYP1B1-, FOXC1-, and MYOC-negative families, we also searched for variants in the other candidate genes reported for CG through WES, but could not find any mutations in these genes. CONCLUSIONS: Our analyses of 29 CG families revealed 9 families with point mutations in the CYP1B1 gene, and four of those patients appeared to be heterozygotes, suggesting the presence of complex pathogenic mechanisms. FOXC1 appears to be another major causal gene of CG, indicating that panel sequencing of CYP1B1 and FOXC1 will be useful for diagnosis of CG in Japanese individuals.
PNPO–PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity

Hiroki Sekine, Haruna Takeda, Norihiko Takeda, Akihiro Kishino, Hayato Anzawa, Takayuki Isagawa, Nao Ohta, Shohei Murakami, Hideya Iwaki, Nobufumi Kato, Shu Kimura, Zun Liu, Koichiro Kato, Fumiki Katsuoka, Masayuki Yamamoto, Fumihito Miura, Takashi Ito, Masatomo Takahashi, Yoshihiro Izumi, Hiroyuki Fujita, Hitoshi Yamagata, Takeshi Bamba, Takaaki Akaike, Norio Suzuki, Kengo Kinoshita, Hozumi Motohashi

Nature Metabolism　2024/05/31
Publisher: Springer Science and Business Media LLC
DOI： 10.1038/s42255-024-01053-4 　

eISSN： 2522-5812
Effects of NRF2 polymorphisms on safety and efficacy of bardoxolone methyl: subanalysis of TSUBAKI study Peer-reviewed

Kazuaki Ikejiri, Takafumi Suzuki, Satsuki Muto, Hirotaka Takama, Kengo Yamawaki, Tatsuya Miyazawa, Itaru Urakawa, Yuichi Aoki, Akihito Otsuki, Fumiki Katsuoka, Kengo Kinoshita, Masaomi Nangaku, Tadao Akizawa, Masayuki Yamamoto

Clinical and Experimental Nephrology　2023/11/14

DOI： 10.1007/s10157-023-02427-w 　
新生児臍帯血の網羅的エピゲノム解析による妊娠初期までの喫煙経験が次世代に及ぼす影響

美辺詩織, 小巻翔平, 大桃秀樹, 高嶋聰, 小野加奈子, 山崎弥生, 須藤洋一, 田高周, 水野聖士, 石黒真美, 工藤久智, 小原拓, 熊田和貴, 勝岡史城, 荻島創一, 木下賢吾, 菅原準一, 栗山進一, 清水厚志

DOHaD研究　11　(3)　37-37　2023/08
Publisher: (一社)日本DOHaD学会
ISSN： 2187-2562

eISSN： 2187-2597
Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice Peer-reviewed

Shimizu R, Hirano I, Hasegawa A, Suzuki M, Otsuki A, Taguchi K, Katsuoka F, Uruno A, Suzuki N, Yumoto A, Okada R, Shrakawa M, Shiba D, Takahashi S, Suzuki T, Yamamoto M

Commun Biol　6　2023/08

DOI： 10.1038/s42003-022-03316-w 　
出生三世代コホートにおける7人家族のエピゲノム研究基盤構築

美辺詩織, 小巻翔平, 大桃秀樹, 高嶋聰, 小野加奈子, 山崎弥生, 須藤洋一, 田高周, 水野聖士, 石黒真美, 工藤久智, 小原拓, 熊田和貴, 勝岡史城, 荻島創一, 木下賢吾, 菅原準一, 栗山進一, 清水厚志

日本抗加齢医学会総会プログラム・抄録集　23回　252-252　2023/06
Publisher: (一社)日本抗加齢医学会
Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

Akiko Saito-Hakoda, Atsuo Kikuchi, Tadahisa Takahashi, Yu Yokoyama, Noriko Himori, Mika Adachi, Ryoukichi Ikeda, Yuri Nomura, Jun Takayama, Junko Kawashima, Fumiki Katsuoka, Fumiyoshi Fujishima, Takehiko Yamaguchi, Akiyo Ito, Takushi Hanita, Junko Kanno, Toshimi Aizawa, Toru Nakazawa, Tetsuaki Kawase, Gen Tamiya, Masayuki Yamamoto, Ikuma Fujiwara, Shigeo Kure

Journal of bone and mineral metabolism　41　(2)　193-202　2022/12/15

DOI： 10.1007/s00774-022-01392-w 　

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INTRODUCTION: Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). MATERIALS AND METHODS: We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. RESULTS: This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. CONCLUSION: Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.
jMorp: Japanese Multi Omics Reference Panel

田高周, 菱沼英史, 井上仁, 青木裕一, 岡村容伸, 川嶋順子, 大槻晃史, 田口恵子, 菅野貴成, 元池育子, 勝岡史城, 小柴生造, 木下賢吾

トーゴーの日2022　1　2022/10/05
Publisher: JST NBDC事業推進部
DOI： 10.18908/togo2022.p040 　
Multiomics and artificial intelligence enabled peripheral blood-based prediction of amnestic mild cognitive impairment

Yota Tatara, Hiromi Yamazaki, Fumiki Katsuoka, Mitsuru Chiba, Daisuke Saigusa, Shuya Kasai, Tomohiro Nakamura, Jin Inoue, Yuichi Aoki, Miho Shoji, Ikuko Motoike, Yoshinori Tamada, Katsuhito Hashizume, Mikio Shoji, Kengo Kinoshita, Koichi Murashita, Shigeyuki Nakaji, Masayuki Yamamoto, Ken Itoh

Current Research in Translational Medicine　71　(1)　103367-103367　2022/10
Publisher: Elsevier BV
DOI： 10.1016/j.retram.2022.103367 　

ISSN： 2452-3186
Selective Elimination of NRF2-Activated Cells by Competition with Neighboring Cells in the Esophageal Epithelium. International-journal

Wataru Hirose, Makoto Horiuchi, Donghan Li, Ikuko N Motoike, Lin Zhang, Hafumi Nishi, Yusuke Taniyama, Takashi Kamei, Mikiko Suzuki, Kengo Kinoshita, Fumiki Katsuoka, Keiko Taguchi, Masayuki Yamamoto

Cellular and molecular gastroenterology and hepatology　15　(1)　153-178　2022/09/14

DOI： 10.1016/j.jcmgh.2022.09.004 　

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BACKGROUND & AIMS: NF-E2-related factor 2 (NRF2) is a transcription factor that regulates cytoprotective gene expression in response to oxidative and electrophilic stresses. NRF2 activity is mainly controlled by Kelch-like ECH-associated protein 1 (KEAP1). Constitutive NRF2 activation by NRF2 mutations or KEAP1 dysfunction results in a poor prognosis for esophageal squamous cell carcinoma (ESCC) through the activation of cytoprotective functions. However, the detailed contributions of NRF2 to ESCC initiation or promotion have not been clarified. Here, we investigated the fate of NRF2-activated cells in the esophageal epithelium. METHODS: We generated tamoxifen-inducible, squamous epithelium-specific Keap1 conditional knockout (Keap1-cKO) mice in which NRF2 was inducibly activated in a subset of cells at the adult stage. Histological, quantitative reverse-transcription polymerase chain reaction (qRT‒PCR), single-cell RNA-sequencing (RNA-seq) and carcinogen experiments were conducted to analyze the Keap1-cKO esophagus. RESULTS: KEAP1-deleted/NRF2-activated cells and cells with normal NRF2 expression (KEAP1-normal cells) coexisted in the Keap1-cKO esophageal epithelium in approximately equal numbers, and NRF2-activated cells formed dysplastic lesions. NRF2-activated cells exhibited weaker attachment to the basement membrane and gradually disappeared from the epithelium. In contrast, neighboring KEAP1-normal cells exhibited accelerated proliferation and started dominating the epithelium but accumulated DNA damage that triggered carcinogenesis upon carcinogen exposure. CONCLUSIONS: Constitutive NRF2 activation promotes the selective elimination of epithelial cells via cell competition, but this competition induces DNA damage in neighboring KEAP1-normal cells, which predisposes them to chemical-induced ESCC.
全ゲノム/全エキソーム解析による生殖細胞系列多型の探索一般住民コホートにおけるBRCA遺伝子バリアントの探索及び結果の回付事業について(Exploration of BRCA1/2 gene variants in a general population cohort and return of genomic results to the participants)

徳永英樹, 安田純, 島田宗昭, 濱中洋平, 重田昌吾, 布施昇男, 勝岡史城, 荻島創一, 山口由美, 寳澤篤, 川目裕, 大根田絹子, 青木洋子, 山本雅之, 八重樫伸生

日本癌学会総会記事　81回　S8-1　2022/09
Publisher: (一社)日本癌学会
ISSN： 0546-0476
The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 Degradation In Vivo. International-journal Peer-reviewed

Ayumi Kuga, Kouhei Tsuchida, Harit Panda, Makoto Horiuchi, Akihito Otsuki, Keiko Taguchi, Fumiki Katsuoka, Mikiko Suzuki, Masayuki Yamamoto

Molecular and cellular biology　42　(7)　e0056321　2022/07/21

DOI： 10.1128/mcb.00563-21 　

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Nrf2 activates cytoprotective gene expression, and Nrf2 activity is regulated through at least two protein degradation pathways: the Keap1-mediated and β-TrCP-mediated pathways. To address the relative contributions of these pathways, we generated knock-in mouse lines expressing an Nrf2SA mutant that harbored two substitution mutations of serine residues interacting with β-TrCP. The homozygous (Nrf2SA/SA) mice grew normally, with Nrf2 levels comparable to those of wild-type (WT) mice under unstressed conditions. However, when Keap1 activity was suppressed, high levels of Nrf2 accumulated in Nrf2SA/SA macrophages compared with that in WT macrophages. We crossed Nrf2SA/SA mice with mice in which Keap1 was knocked down to two different levels. We found that the Nrf2SA/SA mutation induced higher Nrf2 activity when the Keap1 level was strongly reduced, and these mice showed severe growth retardation. However, activation and growth retardation were not evident when Keap1 was moderately suppressed. These increases in Nrf2 activity induced by the Nrf2SA mutation caused severe hyperplasia and hyperkeratosis in the esophageal epithelium but did not cause abnormalities in the other tissues/organs examined. These results indicate that the β-TrCP-mediated pathway cooperates with the Keap1-mediated pathway to regulate Nrf2 activity, which is apparent when the Keap1-mediated pathway is profoundly suppressed.
CEBPB is required for NRF2-mediated drug resistance in NRF2-activated non-small cell lung cancer cells Peer-reviewed

Keito Okazaki, Hayato Anzawa, Fumiki Katsuoka, Kengo Kinoshita, Hiroki Sekine, Hozumi Motohashi

The Journal of Biochemistry　171　(5)　567-578　2022/05/11
Publisher: Oxford University Press (OUP)
DOI： 10.1093/jb/mvac013 　

ISSN： 0021-924X

eISSN： 1756-2651

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Abstract NRF2 is a transcription activator that plays a key role in cytoprotection against oxidative stress. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental, as it drives their malignant progression. We previously found that CCAAT/enhancer-binding protein B (CEBPB) cooperates with NRF2 in NRF2-activated lung cancer and enhances tumour-initiating activity by promoting NOTCH3 expression. However, the general contribution of CEBPB in lung cancer is rather controversial, probably because the role of CEBPB depends on cooperating transcription factors in each cellular context. To understand how NRF2 shapes the function of CEBPB in NRF2-activated lung cancers and its biological consequence, we comprehensively explored NRF2-CEBPB–coregulated genes and found that genes involved in drug metabolism and detoxification were characteristically enriched. Indeed, CEBPB and NRF2 cooperatively contribute to the drug resistance. We also found that CEBPB is directly regulated by NRF2, which is likely to be advantageous for the coexpression and cooperative function of NRF2 and CEBPB. These results suggest that drug resistance of NRF2-activated lung cancers is achieved by the cooperative function of NRF2 and CEBPB.
Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan: The Tohoku Medical Megabank Organization Eye Study. International-journal

Nobuo Fuse, Miyuki Sakurai, Ikuko N Motoike, Kaname Kojima, Takako Takai-Igarashi, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Mami Ishikuro, Taku Obara, Akiko Miyazawa, Kei Homma, Keisuke Ido, Makiko Taira, Tomoko Kobayashi, Ritsuko Shimizu, Akira Uruno, Eiichi N Kodama, Kichiya Suzuki, Yohei Hamanaka, Hiroaki Tomita, Junichi Sugawara, Yoichi Suzuki, Fuji Nagami, Soichi Ogishima, Fumiki Katsuoka, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Yaegashi, Shigeo Kure, Kengo Kinoshita, Masayuki Yamamoto

Ophthalmology science　2　(1)　100113-100113　2022/03

DOI： 10.1016/j.xops.2022.100113 　

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PURPOSE: To elucidate the differences in ocular biometric parameters by generation and gender and to identify axial length (AL)-associated genetic variants in Japanese individuals, we analyzed Tohoku Medical Megabank Organization (ToMMo) Eye Study data. DESIGN: We designed the ToMMo Eye Study, examined AL variations, and conducted genome-wide association studies (GWASs). PARTICIPANTS: In total, 33 483 participants aged > 18 years who were recruited into the community-based cohort (CommCohort) and the birth and three-generation cohort (BirThree Cohort) of the ToMMo Eye Study were examined. METHODS: Each participant was screened with an interview, ophthalmic examinations, and a microarray analysis. The GWASs were performed in 22 379 participants in the CommCohort (discovery stage) and 11 104 participants in the BirThree Cohort (replication stage). We evaluated the associations of single nucleotide polymorphisms (SNPs) with AL using a genome-wide significance threshold (5 × 10-8) in each stage of the study and in the subsequent meta-analysis. MAIN OUTCOME MEASURES: We identified the association of SNPs with AL and distributions of AL in right and left eyes and individuals of different sexes and ages. RESULTS: In the discovery stage, the mean AL of the right eye (23.99 mm) was significantly greater than that of the left eye (23.95 mm). This difference was reproducible across sexes and ages. The GWASs revealed 703 and 215 AL-associated SNPs with genome-wide significance in the discovery and validation stages, respectively, and many of the SNPs in the discovery stage were replicated in the validation stage. Validated SNPs and their associated loci were meta-analyzed for statistical significance (P < 5 × 10-8). This study identified 1478 SNPs spread over 31 loci. Of the 31 loci, 5 are known AL loci, 15 are known refractive-error loci, 4 are known corneal-curvature loci, and 7 loci are newly identified loci that are not known to be associated with AL. Of note, some of them shared functional relationships with previously identified loci. CONCLUSIONS: Our large-scale GWASs exploiting ToMMo Eye Study data identified 31 loci linked to variations in AL, 7 of which are newly reported in this article. The results revealed genetic heterogeneity and similarity in SNPs related to ethnic variations in AL.
Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects. International-journal

Shaili D Patel, Deepti Anand, Hozumi Motohashi, Fumiki Katsuoka, Masayuki Yamamoto, Salil A Lachke

Frontiers in cell and developmental biology　10　981893-981893　2022

DOI： 10.3389/fcell.2022.981893 　

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Deficiency of the small Maf proteins Mafg and Mafk cause multiple defects, namely, progressive neuronal degeneration, cataract, thrombocytopenia and mid-gestational/perinatal lethality. Previous data shows Mafg -/-:Mafk +/- compound knockout (KO) mice exhibit cataracts age 4-months onward. Strikingly, Mafg -/-:Mafk -/- double KO mice develop lens defects significantly early in life, during embryogenesis, but the pathobiology of these defects is unknown, and is addressed here. At embryonic day (E)16.5, the epithelium of lens in Mafg -/-:Mafk -/- animals appears abnormally multilayered as demonstrated by E-cadherin and nuclear staining. Additionally, Mafg -/-:Mafk -/- lenses exhibit abnormal distribution of F-actin near the "fulcrum" region where epithelial cells undergo apical constriction prior to elongation and reorientation as early differentiating fiber cells. To identify the underlying molecular changes, we performed high-throughput RNA-sequencing of E16.5 Mafg -/-:Mafk -/- lenses and identified a cohort of differentially expressed genes that were further prioritized using stringent filtering criteria and validated by RT-qPCR. Several key factors associated with the cytoskeleton, cell cycle or extracellular matrix (e.g., Cdk1, Cdkn1c, Camsap1, Col3a1, Map3k12, Sipa1l1) were mis-expressed in Mafg -/-:Mafk -/- lenses. Further, the congenital cataract-linked extracellular matrix peroxidase Pxdn was significantly overexpressed in Mafg -/-:Mafk -/- lenses, which may cause abnormal cell morphology. These data also identified the ephrin signaling receptor Epha5 to be reduced in Mafg -/-:Mafk -/- lenses. This likely contributes to the Mafg -/-:Mafk -/- multilayered lens epithelium pathology, as loss of an ephrin ligand, Efna5 (ephrin-A5), causes similar lens defects. Together, these findings uncover a novel early function of Mafg and Mafk in lens development and identify their new downstream regulatory relationships with key cellular factors.
dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project. International-journal Peer-reviewed

Soichi Ogishima, Satoshi Nagaie, Satoshi Mizuno, Ryosuke Ishiwata, Keita Iida, Kazuro Shimokawa, Takako Takai-Igarashi, Naoki Nakamura, Sachiko Nagase, Tomohiro Nakamura, Naho Tsuchiya, Naoki Nakaya, Keiko Murakami, Fumihiko Ueno, Tomomi Onuma, Mami Ishikuro, Taku Obara, Shunji Mugikura, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Akito Tsuboi, Shu Tadaka, Fumiki Katsuoka, Akira Narita, Mika Sakurai, Satoshi Makino, Gen Tamiya, Yuichi Aoki, Ritsuko Shimizu, Ikuko N Motoike, Seizo Koshiba, Naoko Minegishi, Kazuki Kumada, Takahiro Nobukuni, Kichiya Suzuki, Inaho Danjoh, Fuji Nagami, Kozo Tanno, Hideki Ohmomo, Koichi Asahi, Atsushi Shimizu, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Fuse, Teiji Tominaga, Shigeo Kure, Nobuo Yaegashi, Kengo Kinoshita, Makoto Sasaki, Hiroshi Tanaka, Masayuki Yamamoto

Human genome variation　8　(1)　44-44　2021/12/10

DOI： 10.1038/s41439-021-00175-5 　

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To reveal gene-environment interactions underlying common diseases and estimate the risk for common diseases, the Tohoku Medical Megabank (TMM) project has conducted prospective cohort studies and genomic and multiomics analyses. To establish an integrated biobank, we developed an integrated database called "dbTMM" that incorporates both the individual cohort/clinical data and the genome/multiomics data of 157,191 participants in the Tohoku Medical Megabank project. To our knowledge, dbTMM is the first database to store individual whole-genome data on a variant-by-variant basis as well as cohort/clinical data for over one hundred thousand participants in a prospective cohort study. dbTMM enables us to stratify our cohort by both genome-wide genetic factors and environmental factors, and it provides a research and development platform that enables prospective analysis of large-scale data from genome cohorts.
Nrf2 plays a critical role in the metabolic response during and after spaceflight. International-journal Peer-reviewed

Akira Uruno, Daisuke Saigusa, Takafumi Suzuki, Akane Yumoto, Tomohiro Nakamura, Naomi Matsukawa, Takahiro Yamazaki, Ristumi Saito, Keiko Taguchi, Mikiko Suzuki, Norio Suzuki, Akihito Otsuki, Fumiki Katsuoka, Eiji Hishinuma, Risa Okada, Seizo Koshiba, Yoshihisa Tomioka, Ritsuko Shimizu, Masaki Shirakawa, Thomas W Kensler, Dai Shiba, Masayuki Yamamoto

Communications biology　4　(1)　1381-1381　2021/12/09

DOI： 10.1038/s42003-021-02904-6 　

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Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by Nrf2 knockout. We conducted metabolome analyses of plasma from wild-type and Nrf2 knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in Nrf2 knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of Nrf2 knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses.
Genetic loci for lung function in Japanese adults with adjustment for exhaled nitric oxide levels as airway inflammation indicator. International-journal Peer-reviewed

Mitsuhiro Yamada, Ikuko N Motoike, Kaname Kojima, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Fumiki Katsuoka, Shu Tadaka, Matsuyuki Shirota, Miyuki Sakurai, Tomohiro Nakamura, Yohei Hamanaka, Kichiya Suzuki, Junichi Sugawara, Soichi Ogishima, Akira Uruno, Eiichi N Kodama, Naoya Fujino, Tadahisa Numakura, Tomohiro Ichikawa, Ayumi Mitsune, Takashi Ohe, Kengo Kinoshita, Masakazu Ichinose, Hisatoshi Sugiura, Masayuki Yamamoto

Communications biology　4　(1)　1288-1288　2021/11/15

DOI： 10.1038/s42003-021-02813-8 　

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Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (NOS2, SPSB2 and RIPOR2) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults.
多層オミックスと機械学習による軽度認知障害の予測モデルの構築

多田羅洋太, 中村智洋, 千葉満, 三枝大輔, 山嵜博未, 勝岡史城, 葛西秋宅, 川瀬倫子, 本間リナ, 松田りら, 藤本哲太, 荘司美穂, 元池育子, 玉田嘉紀, 橋爪克仁, 東海林幹夫, 木下賢吾, 伊東健

Dementia Japan　35　(4)　660-660　2021/10
Publisher: (一社)日本認知症学会
ISSN： 1342-646X
The association between ERK inhibitor sensitivity and molecular characteristics in colorectal cancer. International-journal Peer-reviewed

Hodaka Tayama, Hideaki Karasawa, Akihiro Yamamura, Yasunobu Okamura, Fumiki Katsuoka, Hideyuki Suzuki, Taiki Kajiwara, Minoru Kobayashi, Yuuri Hatsuzawa, Masahiro Shiihara, Li Bin, Md Yeashin Gazi, Mizuki Sato, Kazuki Kumada, Shigehiro Ito, Muneaki Shimada, Toru Furukawa, Takashi Kamei, Shinobu Ohnuma, Michiaki Unno

Biochemical and biophysical research communications　560　59-65　2021/06/30

DOI： 10.1016/j.bbrc.2021.04.130 　

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The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerful in vitro model system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.
GWAS of 9,260 Japanese individuals identified IL4R and the MHC region as associated loci of total serum IgE levels. International-journal Peer-reviewed

Kosuke Shido, Kaname Kojima, Matsuyuki Shirota, Kenshi Yamasaki, Ikuko N Motoike, Atsushi Hozawa, Soichi Ogishima, Naoko Minegishi, Kozo Tanno, Fumiki Katsuoka, Gen Tamiya, Setsuya Aiba, Masayuki Yamamoto, Kengo Kinoshita

The Journal of investigative dermatology　141　(11)　2749-2752　2021/04/14

DOI： 10.1016/j.jid.2021.02.762 　
Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice. International-journal Peer-reviewed

Takahiro Onoki, Yoshihiro Izumi, Masatomo Takahashi, Shohei Murakami, Daisuke Matsumaru, Nao Ohta, Sisca Meida Wati, Nozomi Hatanaka, Fumiki Katsuoka, Mitsuharu Okutsu, Yutaka Yabe, Yoshihiro Hagiwara, Makoto Kanzaki, Takeshi Bamba, Eiji Itoi, Hozumi Motohashi

Redox biology　43　101966-101966　2021/04/05

DOI： 10.1016/j.redox.2021.101966 　

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Skeletal muscle health is important for the prevention of various age-related diseases. The loss of skeletal muscle mass, which is known as sarcopenia, underlies physical disability, poor quality of life and chronic diseases in elderly people. The transcription factor NRF2 plays important roles in the regulation of the cellular defense against oxidative stress, as well as the metabolism and mitochondrial activity. To determine the contribution of skeletal muscle NRF2 to exercise capacity, we conducted skeletal muscle-specific inhibition of KEAP1, which is a negative regulator of NRF2, and examined the cell-autonomous and non-cell-autonomous effects of NRF2 pathway activation in skeletal muscles. We found that NRF2 activation in skeletal muscles increased slow oxidative muscle fiber type and improved exercise endurance capacity in female mice. We also observed that female mice with NRF2 pathway activation in their skeletal muscles exhibited enhanced exercise-induced mobilization and β-oxidation of fatty acids. These results indicate that NRF2 activation in skeletal muscles promotes communication with adipose tissues via humoral and/or neuronal signaling and facilitates the utilization of fatty acids as an energy source, resulting in increased mitochondrial activity and efficient energy production during exercise, which leads to improved exercise endurance.
Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability Peer-reviewed

Y. Nagayoshi, T. Chujo, S. Hirata, H. Nakatsuka, C.-W. Chen, M. Takakura, K. Miyauchi, Y. Ikeuchi, B. C. Carlyle, R. R. Kitchen, T. Suzuki, F. Katsuoka, M. Yamamoto, Y. Goto, M. Tanaka, K. Natsume, A. C. Nairn, T. Suzuki, K. Tomizawa, F.-Y. Wei

Science Advances　7　(13)　eabf3072-eabf3072　2021/03
Publisher: American Association for the Advancement of Science (AAAS)
DOI： 10.1126/sciadv.abf3072 　

eISSN： 2375-2548

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<italic>FtsJ RNA 2′-O-methyltransferase 1</italic>(<italic>FTSJ1</italic>) gene has been implicated in X-linked intellectual disability (XLID), but the molecular pathogenesis is unknown. We show that Ftsj1 is responsible for 2′-<italic>O</italic>-methylation of 11 species of cytosolic transfer RNAs (tRNAs) at the anticodon region, and these modifications are abolished in Ftsj1 knockout (KO) mice and XLID patient–derived cells. Loss of 2′-<italic>O</italic>-methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNA^Phein the brain, resulting in a slow decoding at Phe codons. Ribosome profiling showed that translation efficiency is significantly reduced in a subset of genes that need to be efficiently translated to support synaptic organization and functions. Ftsj1 KO mice display immature synaptic morphology and aberrant synaptic plasticity, which are associated with anxiety-like and memory deficits. The data illuminate a fundamental role of tRNA modification in the brain through regulation of translation efficiency and provide mechanistic insights into FTSJ1-related XLID.
Identification of Dominant Transcripts in Oxidative Stress Response by a Full-Length Transcriptome Analysis. International-journal Peer-reviewed

Akihito Otsuki, Yasunobu Okamura, Yuichi Aoki, Noriko Ishida, Kazuki Kumada, Naoko Minegishi, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

Molecular and cellular biology　41　(2)　2021/01/25

DOI： 10.1128/MCB.00472-20 　

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Our body responds to environmental stress by changing the expression levels of a series of cytoprotective enzymes/proteins through multilayered regulatory mechanisms, including the KEAP1-NRF2 system. While NRF2 upregulates the expression of many cytoprotective genes, there are fundamental limitations in short-read RNA sequencing (RNA-Seq), resulting in confusion regarding interpreting the effectiveness of cytoprotective gene induction at the transcript level. To precisely delineate isoform usage in the stress response, we conducted independent full-length transcriptome profiling (isoform sequencing; Iso-Seq) analyses of lymphoblastoid cells from three volunteers under normal and electrophilic stress-induced conditions. We first determined the first exon usage in KEAP1 and NFE2L2 (encoding NRF2) and found the presence of transcript diversity. We then examined changes in isoform usage of NRF2 target genes under stress conditions and identified a few isoforms dominantly expressed in the majority of NRF2 target genes. The expression levels of isoforms determined by Iso-Seq analyses showed striking differences from those determined by short-read RNA-Seq; the latter could be misleading concerning the abundance of transcripts. These results support that transcript usage is tightly regulated to produce functional proteins under electrophilic stress. Our present study strongly argues that there are important benefits that can be achieved by long-read transcriptome sequencing.
jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population. International-journal Peer-reviewed

Shu Tadaka, Eiji Hishinuma, Shohei Komaki, Ikuko N Motoike, Junko Kawashima, Daisuke Saigusa, Jin Inoue, Jun Takayama, Yasunobu Okamura, Yuichi Aoki, Matsuyuki Shirota, Akihito Otsuki, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

Nucleic acids research　49　(D1)　D536-D544　2021/01/08

DOI： 10.1093/nar/gkaa1034 　

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In the Tohoku Medical Megabank project, genome and omics analyses of participants in two cohort studies were performed. A part of the data is available at the Japanese Multi Omics Reference Panel (jMorp; https://jmorp.megabank.tohoku.ac.jp) as a web-based database, as reported in our previous manuscript published in Nucleic Acid Research in 2018. At that time, jMorp mainly consisted of metabolome data; however, now genome, methylome, and transcriptome data have been integrated in addition to the enhancement of the number of samples for the metabolome data. For genomic data, jMorp provides a Japanese reference sequence obtained using de novo assembly of sequences from three Japanese individuals and allele frequencies obtained using whole-genome sequencing of 8,380 Japanese individuals. In addition, the omics data include methylome and transcriptome data from ∼300 samples and distribution of concentrations of more than 755 metabolites obtained using high-throughput nuclear magnetic resonance and high-sensitivity mass spectrometry. In summary, jMorp now provides four different kinds of omics data (genome, methylome, transcriptome, and metabolome), with a user-friendly web interface. This will be a useful scientific data resource on the general population for the discovery of disease biomarkers and personalized disease prevention and early diagnosis.
Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2). International-journal Peer-reviewed

Hideki Tokunaga, Keita Iida, Atsushi Hozawa, Soichi Ogishima, Yoh Watanabe, Shogo Shigeta, Muneaki Shimada, Yumi Yamaguchi-Kabata, Shu Tadaka, Fumiki Katsuoka, Shin Ito, Kazuki Kumada, Yohei Hamanaka, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda

PloS one　16　(1)　e0236907　2021

DOI： 10.1371/journal.pone.0236907 　

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Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study.
Landscape of electrophilic and inflammatory stress-mediated gene regulation in human lymphoblastoid cell lines. International-journal Peer-reviewed

Noriko Ishida, Yuichi Aoki, Fumiki Katsuoka, Ichiko Nishijima, Takahiro Nobukuni, Hayato Anzawa, Li Bin, Miyuki Tsuda, Kazuki Kumada, Hisaaki Kudo, Takahiro Terakawa, Akihito Otsuki, Kengo Kinoshita, Riu Yamashita, Naoko Minegishi, Masayuki Yamamoto

Free radical biology & medicine　161　71-83　2020/12

DOI： 10.1016/j.freeradbiomed.2020.09.023 　

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Human lymphoblastoid cell lines (LCLs) are valuable for the functional analyses of diseases. We have established more than 4200 LCLs as one of the resources of an integrated biobank. While oxidative and inflammatory stresses play critical roles in the onset and progression of various diseases, the responsiveness of LCLs, especially that of biobank-made LCLs, to these stresses has not been established. To address how LCLs respond to these stresses, in this study, we performed RNA sequencing of eleven human LCLs that were treated with an electrophile, diethyl maleate (DEM) and/or an inflammatory mediator, lipopolysaccharide (LPS). We found that over two thousand genes, including those regulated by a master regulator of the electrophilic/oxidative stress response, NRF2, were upregulated in LCLs treated with DEM, while approximately three hundred genes, including inflammation-related genes, were upregulated in LPS-treated LCLs. Of the LPS-induced genes, a subset of proinflammatory genes was repressed by DEM, supporting the notion that DEM suppresses the expression of proinflammatory genes through NRF2 activation. Conversely, a part of DEM-induced gene was repressed by LPS, suggesting reciprocal interference between electrophilic and inflammatory stress-mediated pathways. These data clearly demonstrate that LCLs maintain, by and large, responsive pathways against oxidative and inflammatory stresses and further endorse the usefulness of the LCL supply from the biobank.
Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers. International-journal Peer-reviewed

Keito Okazaki, Hayato Anzawa, Zun Liu, Nao Ota, Hiroshi Kitamura, Yoshiaki Onodera, Md Morshedul Alam, Daisuke Matsumaru, Takuma Suzuki, Fumiki Katsuoka, Shu Tadaka, Ikuko Motoike, Mika Watanabe, Kazuki Hayasaka, Akira Sakurada, Yoshinori Okada, Masayuki Yamamoto, Takashi Suzuki, Kengo Kinoshita, Hiroki Sekine, Hozumi Motohashi

Nature communications　11　(1)　5911-5911　2020/11/20

DOI： 10.1038/s41467-020-19593-0 　

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Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.
Analysis of HLA-G long-read genomic sequences in mother-offspring pairs with preeclampsia. International-journal Peer-reviewed

Ayako Nishizawa, Kazuki Kumada, Keiko Tateno, Maiko Wagata, Sakae Saito, Fumiki Katsuoka, Satoshi Mizuno, Soichi Ogishima, Masayuki Yamamoto, Jun Yasuda, Junichi Sugawara

Scientific reports　10　(1)　20027-20027　2020/11/18

DOI： 10.1038/s41598-020-77081-3 　

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Preeclampsia is a pregnancy-induced disorder that is characterized by hypertension and is a leading cause of perinatal and maternal-fetal morbidity and mortality. HLA-G is thought to play important roles in maternal-fetal immune tolerance, and the associations between HLA-G gene polymorphisms and the onset of pregnancy-related diseases have been explored extensively. Because contiguous genomic sequencing is difficult, the association between the HLA-G genotype and preeclampsia onset is controversial. In this study, genomic sequences of the HLA-G region (5.2 kb) from 31 pairs of mother-offspring genomic DNA samples (18 pairs from normal pregnancies/births and 13 from preeclampsia births) were obtained by single-molecule real-time sequencing using the PacBio RS II platform. The HLA-G alleles identified in our cohort matched seven known HLA-G alleles, but we also identified two new HLA-G alleles at the fourth-field resolution and compared them with nucleotide sequences from a public database that consisted of coding sequences that cover the 3.1-kb HLA-G gene span. Intriguingly, a potential association between preeclampsia onset and the poly T stretch within the downstream region of the HLA-G*01:01:01:01 allele was found. Our study suggests that long-read sequencing of HLA-G will provide clues for characterizing HLA-G variants that are involved in the pathophysiology of preeclampsia.
Identification of critical genetic variants associated with metabolic phenotypes of the Japanese population. International-journal Peer-reviewed

Seizo Koshiba, Ikuko N Motoike, Daisuke Saigusa, Jin Inoue, Yuichi Aoki, Shu Tadaka, Matsuyuki Shirota, Fumiki Katsuoka, Gen Tamiya, Naoko Minegishi, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto

Communications biology　3　(1)　662-662　2020/11/11

DOI： 10.1038/s42003-020-01383-5 　

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We performed a metabolome genome-wide association study for the Japanese population in the prospective cohort study of Tohoku Medical Megabank. By combining whole-genome sequencing and nontarget metabolome analyses, we identified a large number of novel associations between genetic variants and plasma metabolites. Of the identified metabolite-associated genes, approximately half have already been shown to be involved in various diseases. We identified metabolite-associated genes involved in the metabolism of xenobiotics, some of which are from intestinal microorganisms, indicating that the identified genetic variants also markedly influence the interaction between the host and symbiotic bacteria. We also identified five associations that appeared to be female-specific. A number of rare variants that influence metabolite levels were also found, and combinations of common and rare variants influenced the metabolite levels more profoundly. These results support our contention that metabolic phenotyping provides important insights into how genetic and environmental factors provoke human diseases.
A genotype imputation method for de-identified haplotype reference information by using recurrent neural network. International-journal Peer-reviewed

Kaname Kojima, Shu Tadaka, Fumiki Katsuoka, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

PLoS computational biology　16　(10)　e1008207　2020/10

DOI： 10.1371/journal.pcbi.1008207 　

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Genotype imputation estimates the genotypes of unobserved variants using the genotype data of other observed variants based on a collection of haplotypes for thousands of individuals, which is known as a haplotype reference panel. In general, more accurate imputation results were obtained using a larger size of haplotype reference panel. Most of the existing genotype imputation methods explicitly require the haplotype reference panel in precise form, but the accessibility of haplotype data is often limited, due to the requirement of agreements from the donors. Since de-identified information such as summary statistics or model parameters can be used publicly, imputation methods using de-identified haplotype reference information might be useful to enhance the quality of imputation results under the condition where the access of the haplotype data is limited. In this study, we proposed a novel imputation method that handles the reference panel as its model parameters by using bidirectional recurrent neural network (RNN). The model parameters are presented in the form of de-identified information from which the restoration of the genotype data at the individual-level is almost impossible. We demonstrated that the proposed method provides comparable imputation accuracy when compared with the existing imputation methods using haplotype datasets from the 1000 Genomes Project (1KGP) and the Haplotype Reference Consortium. We also considered a scenario where a subset of haplotypes is made available only in de-identified form for the haplotype reference panel. In the evaluation using the 1KGP dataset under the scenario, the imputation accuracy of the proposed method is much higher than that of the existing imputation methods. We therefore conclude that our RNN-based method is quite promising to further promote the data-sharing of sensitive genome data under the recent movement for the protection of individuals' privacy.
Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer. International-journal Peer-reviewed

Yingsong Lin, Masahiro Nakatochi, Yasuyuki Hosono, Hidemi Ito, Yoichiro Kamatani, Akihito Inoko, Hiromi Sakamoto, Fumie Kinoshita, Yumiko Kobayashi, Hiroshi Ishii, Masato Ozaka, Takashi Sasaki, Masato Matsuyama, Naoki Sasahira, Manabu Morimoto, Satoshi Kobayashi, Taito Fukushima, Makoto Ueno, Shinichi Ohkawa, Naoto Egawa, Sawako Kuruma, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Masumi Okuda, Takako Osaki, Shigeru Kamiya, Chaochen Wang, Kazuo Hara, Yasuhiro Shimizu, Tatsuo Miyamoto, Yuko Hayashi, Hiromichi Ebi, Tomohiro Kohmoto, Issei Imoto, Yumiko Kasugai, Yoshinori Murakami, Masato Akiyama, Kazuyoshi Ishigaki, Koichi Matsuda, Makoto Hirata, Kazuaki Shimada, Takuji Okusaka, Takahisa Kawaguchi, Meiko Takahashi, Yoshiyuki Watanabe, Kiyonori Kuriki, Aya Kadota, Rieko Okada, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Atsushi Goto, Kengo Kinoshita, Nobuo Fuse, Fumiki Katsuoka, Atsushi Shimizu, Satoshi S Nishizuka, Kozo Tanno, Ken Suzuki, Yukinori Okada, Momoko Horikoshi, Toshimasa Yamauchi, Takashi Kadowaki, Herbert Yu, Jun Zhong, Laufey T Amundadottir, Yuichiro Doki, Hideshi Ishii, Hidetoshi Eguchi, David Bogumil, Christopher A Haiman, Loic Le Marchand, Masaki Mori, Harvey Risch, Veronica W Setiawan, Shoichiro Tsugane, Kenji Wakai, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo

Nature communications　11　(1)　3175-3175　2020/06/24

DOI： 10.1038/s41467-020-16711-w 　

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Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10-8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.
Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy International-journal Peer-reviewed

Matsuyuki Shirota, Daisuke Saigusa, Riu Yamashita, Yasutake Kato, Mitsuyo Matsumoto, Junya Yamagishi, Noriko Ishida, Kazuki Kumada, Yuji Oe, Hisaaki Kudo, Junji Yokozawa, Yoko Kuroki, Ikuko Motoike, Fumiki Katsuoka, Masao Nagasaki, Seizo Koshiba, Keiko Nakayama, Osamu Tanabe, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Hirohito Metoki, Shinichi Kuriyama, Nobuo Yaegashi, Masayuki Yamamoto, Junichi Sugawara

Medical Mass Spectrometry　4　(1)　36-49　2020/04/16

DOI： 10.24508/mms.2020.06.001 　
Impacts of NRF2 activation in non-small-cell lung cancer cell lines on extracellular metabolites. International-journal Peer-reviewed

Daisuke Saigusa, Ikuko N Motoike, Sakae Saito, Michael Zorzi, Yuichi Aoki, Hiroshi Kitamura, Mikiko Suzuki, Fumiki Katsuoka, Hirofumi Ishii, Kengo Kinoshita, Hozumi Motohashi, Masayuki Yamamoto

Cancer science　111　(2)　667-678　2020/02

DOI： 10.1111/cas.14278 　

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Aberrant activation of NRF2 is as a critical prognostic factor that drives the malignant progression of various cancers. Cancer cells with persistent NRF2 activation heavily rely on NRF2 activity for therapeutic resistance and aggressive tumorigenic capacity. To clarify the metabolic features of NRF2-activated lung cancers, we conducted targeted metabolomic (T-Met) and global metabolomic (G-Met) analyses of non-small-cell lung cancer (NSCLC) cell lines in combination with exome and transcriptome analyses. Exome analysis of 88 cell lines (49 adenocarcinoma, 14 large cell carcinoma, 15 squamous cell carcinoma and 10 others) identified non-synonymous mutations in the KEAP1, NRF2 and CUL3 genes. Judging from the elevated expression of NRF2 target genes, these mutations are expected to result in the constitutive stabilization of NRF2. Out of the 88 cell lines, 52 NSCLC cell lines (29 adenocarcinoma, 10 large cell carcinoma, 9 squamous cell carcinoma and 4 others) were subjected to T-Met analysis. Classification of the 52 cell lines into three groups according to the NRF2 target gene expression enabled us to draw typical metabolomic signatures induced by NRF2 activation. From the 52 cell lines, 18 NSCLC cell lines (14 adenocarcinoma, 2 large cell carcinoma, 1 squamous cell carcinoma and 1 others) were further chosen for G-Met and detailed transcriptome analyses. G-Met analysis of their culture supernatants revealed novel metabolites associated with NRF2 activity, which may be potential diagnostic biomarkers of NRF2 activation. This study also provides useful information for the exploration of new metabolic nodes for selective toxicity towards NRF2-activated NSCLC.
Establishment of Integrated Biobank for Precision Medicine and Personalized Healthcare: The Tohoku Medical Megabank Project. Peer-reviewed

Nobuo Fuse, Mika Sakurai-Yageta, Fumiki Katsuoka, Inaho Danjoh, Ritsuko Shimizu, Gen Tamiya, Fuji Nagami, Hiroshi Kawame, Shinichi Higuchi, Kengo Kinoshita, Shigeo Kure, Masayuki Yamamoto

JMA journal　2　(2)　113-122　2019/09/04

DOI： 10.31662/jmaj.2019-0014 　

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The Tohoku Medical Megabank (TMM) project was established to provide creative reconstruction of the Tohoku area that suffered from a huge earthquake and ensuing tsunami (the Great East Japan Earthquake, GEJE). TMM aims to establish two large-scale genome cohorts and an integrated biobank managing biospecimen and related information. It supports community medicine by establishing next-generation medical systems through a combination of the prospective genome cohort studies with a total of 150,000 participants and genomic medicine. The strategies for genome analyses in TMM are to develop an elaborate genome reference panel by means of high-fidelity Japanese whole-genome sequence, to design custom single nucleotide polymorphism (SNP) arrays based on the reference panel, and to obtain genotype data for all the TMM cohort participants subsequently. Disease-associated genomic information and omics data, including metabolomics and microbiome analysis, provide an essential platform for precision medicine and personalized healthcare (PHC). Ethical, legal, and social issues (ELSI) and education are important for implementing genomic medicine. The major considerations of ELSI regarding each participant of the cohort studies are the respect for the autonomy and the protection of privacies. Moreover, developing and provide human resources not only for the TMM project but also for the social implementation of precision medicine and PHC is required. We started a pilot study of the return of genomic results for familial hypercholesterolemia (FH) as a target disease. TMM aims to establish solid platforms that support precision medicine and PHC based on the genomic and omics information and environmental and lifestyle factors of the individuals, which is one of the most advanced medical care beyond the evidenced-based medicine in the near future.
Biobank Establishment and Sample Management in the Tohoku Medical Megabank Project. Peer-reviewed

Naoko Minegishi, Ichiko Nishijima, Takahiro Nobukuni, Hisaaki Kudo, Noriko Ishida, Takahiro Terakawa, Kazuki Kumada, Riu Yamashita, Fumiki Katsuoka, Soichi Ogishima, Kichiya Suzuki, Makoto Sasaki, Mamoru Satoh, Tohoku Medical Megabank Project Study Group, Masayuki Yamamoto

The Tohoku journal of experimental medicine　248　(1)　45-55　2019/05
Publisher: Tohoku University Medical Press
DOI： 10.1620/tjem.248.45 　

ISSN： 0040-8727

eISSN： 1349-3329

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The Tohoku Medical Megabank biobank (TMM biobank) is the first major population-based biobank established in Japan. The TMM biobank was established based on two population cohorts and is a reconstruction program from the Great East Japan Earthquake and Tsunami of 2011. The biobank stores more than 3.4 million tubes of biospecimens and associated health and analytic data obtained from approximately 150,000 TMM cohort participants between May 2013 and December 2018, and the TMM biobank currently shares high-quality specimens and data. Various biospecimens, including peripheral and cord blood mononuclear cells, buffy coat, plasma, serum, urine, breast milk and saliva have been collected in the TMM biobank. To minimize human error and maintain the quality of data and specimens, we have been utilizing laboratory information management system into various biobank procedures from registration to storage with various automation systems, such as liquid dispensing, DNA extraction and their storage. The biobank procedures for the quality management system (ISO 9001:2015) and information security management system (ISO 27001:2013) are certified by the International Organization for Standardization. The quality of our biobank samples fulfills the pre-analytical requirements for researchers conducting next-generation whole genome sequencing, DNA array analyses, proteomics, metabolomics, etc. We established analytical centers to conduct standard genomic and multiomic analyses in-house and share the generated data. Additionally, we generate thousands of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and proliferating T cells for functional studies. The TMM biobank serves as an indispensable infrastructure for academic, clinical and industrial research to actualize next-generation medicine in Japan.
Nrf2 activation in myeloid cells and endothelial cells differentially mitigates sickle cell disease pathology in mice. International-journal Peer-reviewed

Nadine Keleku-Lukwete, Mikiko Suzuki, Harit Panda, Akihito Otsuki, Fumiki Katsuoka, Ritsumi Saito, Daisuke Saigusa, Akira Uruno, Masayuki Yamamoto

Blood advances　3　(8)　1285-1297　2019/04/23

DOI： 10.1182/bloodadvances.2018017574 　

ISSN： 2473-9529

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Sickle cell disease (SCD) is caused by a monogenic mutation of the β-globin gene and affects millions of people worldwide. SCD is associated with sustained hemolytic anemia, vasoocclusion, ischemia-reperfusion injury, oxidative tissue damage, inflammatory cell activation, and systemic endothelial dysfunction. The transcription factor Nrf2 coordinates the expression of a wide variety of genes encoding antioxidant, detoxification, and metabolic enzymes. Nrf2 participates in suppressing proinflammatory cytokines and organ protection in SCD. However, little is known regarding the mechanisms by which Nrf2 ameliorates SCD pathology or how some cells respond to Nrf2 stimuli to alleviate SCD pathology. Here, we asked whether monocytes/granulocytes and/or endothelial cells are particularly critical in alleviating the pathology of SCD. By targeting these cells with a Cre recombinase system, we generated SCD::Keap1F/F::LysM-Cre and Tie1-Cre mice with constitutive Nrf2 activation in monocytes/granulocytes and endothelial cells, respectively. Analyses of SCD::Keap1F/F::LysM-Cre and SCD::Keap1F/F::Tie1-Cre mice revealed significantly reduced inflammation, along with decreased white blood cell counts and lower Tnfα and Il1β expression in the lungs. Notably, SCD::Keap1F/F::LysM-Cre mice exhibited reduced heme distribution in the liver, consistent with a decrease in the damaged areas. Vascular function in SCD::Keap1F/F::Tie1-Cre mice was significantly improved, with a 50% decrease in vascular leakage and low expression of the adhesion molecules Vcam1 and P-selectin. Thus, Nrf2 activation in monocytes/granulocytes and endothelial cells contributes differentially and cooperatively to the improvement of SCD pathology.
Construction of full-length Japanese reference panel of class I HLA genes with single-molecule, real-time sequencing. International-journal Peer-reviewed

Takahiro Mimori, Jun Yasuda, Yoko Kuroki, Tomoko F Shibata, Fumiki Katsuoka, Sakae Saito, Naoki Nariai, Akira Ono, Naomi Nakai-Inagaki, Kazuharu Misawa, Keiko Tateno, Yosuke Kawai, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Kichiya Suzuki, Kengo Kinoshita, Masao Nagasaki, Masayuki Yamamoto

The pharmacogenomics journal　19　(2)　136-146　2019/04
Publisher: Springer Nature
DOI： 10.1038/s41397-017-0010-4 　

ISSN： 1470-269X

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Human leukocyte antigen (HLA) is a gene complex known for its exceptional diversity across populations, importance in organ and blood stem cell transplantation, and associations of specific alleles with various diseases. We constructed a Japanese reference panel of class I HLA genes (ToMMo HLA panel), comprising a distinct set of HLA-A, HLA-B, HLA-C, and HLA-H alleles, by single-molecule, real-time (SMRT) sequencing of 208 individuals included in the 1070 whole-genome Japanese reference panel (1KJPN). For high-quality allele reconstruction, we developed a novel pipeline, Primer-Separation Assembly and Refinement Pipeline (PSARP), in which the SMRT sequencing and additional short-read data were used. The panel consisted of 139 alleles, which were all extended from known IPD-IMGT/HLA sequences, contained 40 with novel variants, and captured more than 96.5% of allelic diversity in 1KJPN. These newly available sequences would be important resources for research and clinical applications including high-resolution HLA typing, genetic association studies, and analyzes of cis-regulatory elements.
Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A. International-journal Peer-reviewed

Mina Dodo, Hiroshi Kitamura, Hiroki Shima, Daisuke Saigusa, Sisca Meida Wati, Nao Ota, Fumiki Katsuoka, Hatsune Chiba, Hiroaki Okae, Takahiro Arima, Kazuhiko Igarashi, Takeyoshi Koseki, Hiroki Sekine, Hozumi Motohashi

Journal of biochemistry　165　(4)　323-334　2019/04/01

DOI： 10.1093/jb/mvy108 　

ISSN： 0021-924X

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Metabolites are sensitive indicators of moment-to-moment cellular status and activity. Expecting that tissue-specific metabolic signatures unveil a unique function of the tissue, we examined metabolomes of mouse liver and testis and found that an unusual metabolite, 2-hydroxyglutarate (2-HG), was abundantly accumulated in the testis. 2-HG can exist as D- or L-enantiomer, and both enantiomers interfere with the activities of 2-oxoglutarate (2-OG)-dependent dioxygenases, such as the Jumonji family of histone demethylases. Whereas D-2-HG is produced by oncogenic mutants of isocitrate dehydrogenases (IDH) and known as an oncometabolite, L-2-HG was the major enantiomer detected in the testis, suggesting that a distinct mechanism underlies the testicular production of this metabolite. We clarified that lactate dehydrogenase C (LDHC), a testis-specific lactate dehydrogenase, is responsible for L-2-HG accumulation by generating and analysing Ldhc-deficient mice. Although the inhibitory effects of 2-HG on 2-OG-dependent dioxygenases were barely observed in the testis, the LDHA protein level was remarkably decreased in Ldhc-deficient sperm, indicating that LDHC is required for LDHA expression in the sperm. This unique functional interaction between LDH family members supports lactate dehydrogenase activity in the sperm. The severely impaired motility of Ldhc-deficient sperm suggests a substantial contribution of glycolysis to energy production for sperm motility.
Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. International-journal Peer-reviewed

Yumi Yamaguchi-Kabata, Jun Yasuda, Akira Uruno, Kazuro Shimokawa, Seizo Koshiba, Yoichi Suzuki, Nobuo Fuse, Hiroshi Kawame, Shu Tadaka, Masao Nagasaki, Kaname Kojima, Fumiki Katsuoka, Kazuki Kumada, Osamu Tanabe, Gen Tamiya, Nobuo Yaegashi, Kengo Kinoshita, Masayuki Yamamoto, Shigeo Kure

Human genetics　138　(4)　389-409　2019/04

DOI： 10.1007/s00439-019-01998-7 　

ISSN： 0340-6717

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Incidence rates of Mendelian diseases vary among ethnic groups, and frequencies of variant types of causative genes also vary among human populations. In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Focusing on 32 genes for 17 congenital metabolic disorders included in newborn screening (NBS) in Japan, we identified reported and predicted pathogenic variants through variant annotation, interpretation, and multiple ways of classifications. The estimated carrier frequencies were compared with those from the Japanese NBS data based on 1,949,987 newborns from a previous study. The estimated carrier frequency based on genomic data with a recent guideline of variant interpretation for the PAH gene, in which defects cause hyperphenylalaninemia (HPA) and phenylketonuria (PKU), provided a closer estimate to that by the observed incidence than the other methods. In contrast, the estimated carrier frequencies for SLC25A13, which causes citrin deficiency, were much higher compared with the incidence rate. The results varied greatly among the 11 NBS diseases with single responsible genes; the possible reasons for departures from the carrier frequencies by reported incidence rates were discussed. Of note, (1) the number of pathogenic variants increases by including additional lines of evidence, (2) common variants with mild effects also contribute to the actual frequency of patients, and (3) penetrance of each variant remains unclear.
Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy. International-journal Peer-reviewed

Junichi Sugawara, Daisuke Ochi, Riu Yamashita, Takafumi Yamauchi, Daisuke Saigusa, Maiko Wagata, Taku Obara, Mami Ishikuro, Yoshiki Tsunemoto, Yuki Harada, Tomoko Shibata, Takahiro Mimori, Junko Kawashima, Fumiki Katsuoka, Takako Igarashi-Takai, Soichi Ogishima, Hirohito Metoki, Hiroaki Hashizume, Nobuo Fuse, Naoko Minegishi, Seizo Koshiba, Osamu Tanabe, Shinichi Kuriyama, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto, Satoshi Hiyama, Masao Nagasaki

BMJ open　9　(2)　e025939　2019/02/19

DOI： 10.1136/bmjopen-2018-025939 　

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PURPOSE: A prospective cohort study for pregnant women, the Maternity Log study, was designed to construct a time-course high-resolution reference catalogue of bioinformatic data in pregnancy and explore the associations between genomic and environmental factors and the onset of pregnancy complications, such as hypertensive disorders of pregnancy, gestational diabetes mellitus and preterm labour, using continuous lifestyle monitoring combined with multiomics data on the genome, transcriptome, proteome, metabolome and microbiome. PARTICIPANTS: Pregnant women were recruited at the timing of first routine antenatal visits at Tohoku University Hospital, Sendai, Japan, between September 2015 and November 2016. Of the eligible women who were invited, 65.4% agreed to participate, and a total of 302 women were enrolled. The inclusion criteria were age ≥20 years and the ability to access the internet using a smartphone in the Japanese language. FINDINGS TO DATE: Study participants uploaded daily general health information including quality of sleep, condition of bowel movements and the presence of nausea, pain and uterine contractions. Participants also collected physiological data, such as body weight, blood pressure, heart rate and body temperature, using multiple home healthcare devices. The mean upload rate for each lifelog item was ranging from 67.4% (fetal movement) to 85.3% (physical activity), and the total number of data points was over 6 million. Biospecimens, including maternal plasma, serum, urine, saliva, dental plaque and cord blood, were collected for multiomics analysis. FUTURE PLANS: Lifelog and multiomics data will be used to construct a time-course high-resolution reference catalogue of pregnancy. The reference catalogue will allow us to discover relationships among multidimensional phenotypes and novel risk markers in pregnancy for the future personalised early prediction of pregnancy complications.
Genome analyses for the Tohoku Medical Megabank Project towards establishment of personalized healthcare. International-journal Peer-reviewed

Jun Yasuda, Kengo Kinoshita, Fumiki Katsuoka, Inaho Danjoh, Mika Sakurai-Yageta, Ikuko N Motoike, Yoko Kuroki, Sakae Saito, Kaname Kojima, Matsuyuki Shirota, Daisuke Saigusa, Akihito Otsuki, Junko Kawashima, Yumi Yamaguchi-Kabata, Shu Tadaka, Yuichi Aoki, Takahiro Mimori, Kazuki Kumada, Jin Inoue, Satoshi Makino, Miho Kuriki, Nobuo Fuse, Seizo Koshiba, Osamu Tanabe, Masao Nagasaki, Gen Tamiya, Ritsuko Shimizu, Takako Takai-Igarashi, Soichi Ogishima, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Akito Tsuboi, Hideyasu Kiyomoto, Tadashi Ishii, Hiroaki Tomita, Naoko Minegishi, Yoichi Suzuki, Kichiya Suzuki, Hiroshi Kawame, Hiroshi Tanaka, Yasuyuki Taki, Nobuo Yaegashi, Shigeo Kure, Fuji Nagami, Kenjiro Kosaki, Yoichi Sutoh, Tsuyoshi Hachiya, Atsushi Shimizu, Makoto Sasaki, Masayuki Yamamoto

Journal of biochemistry　165　(2)　139-158　2019/02/01

DOI： 10.1093/jb/mvy096 　

ISSN： 0021-924X

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Personalized healthcare (PHC) based on an individual's genetic make-up is one of the most advanced, yet feasible, forms of medical care. The Tohoku Medical Megabank (TMM) Project aims to combine population genomics, medical genetics and prospective cohort studies to develop a critical infrastructure for the establishment of PHC. To date, a TMM CommCohort (adult general population) and a TMM BirThree Cohort (birth+three-generation families) have conducted recruitments and baseline surveys. Genome analyses as part of the TMM Project will aid in the development of a high-fidelity whole-genome Japanese reference panel, in designing custom single-nucleotide polymorphism (SNP) arrays specific to Japanese, and in estimation of the biological significance of genetic variations through linked investigations of the cohorts. Whole-genome sequencing from >3,500 unrelated Japanese and establishment of a Japanese reference genome sequence from long-read data have been done. We next aim to obtain genotype data for all TMM cohort participants (>150,000) using our custom SNP arrays. These data will help identify disease-associated genomic signatures in the Japanese population, while genomic data from TMM BirThree Cohort participants will be used to improve the reference genome panel. Follow-up of the cohort participants will allow us to test the genetic markers and, consequently, contribute to the realization of PHC.
Construction of JRG (Japanese reference genome) with single-molecule real-time sequencing. International-journal Peer-reviewed

Masao Nagasaki, Yoko Kuroki, Tomoko F Shibata, Fumiki Katsuoka, Takahiro Mimori, Yosuke Kawai, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Yoichi Suzuki, Hiroshi Kawame, Fuji Nagami, Takako Takai-Igarashi, Soichi Ogishima, Kaname Kojima, Kazuharu Misawa, Osamu Tanabe, Nobuo Fuse, Hiroshi Tanaka, Nobuo Yaegashi, Kengo Kinoshita, Shiego Kure, Jun Yasuda, Masayuki Yamamoto

Human genome variation　6　27-27　2019

DOI： 10.1038/s41439-019-0057-7 　

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In recent genome analyses, population-specific reference panels have indicated important. However, reference panels based on short-read sequencing data do not sufficiently cover long insertions. Therefore, the nature of long insertions has not been well documented. Here, we assembled a Japanese genome using single-molecule real-time sequencing data and characterized insertions found in the assembled genome. We identified 3691 insertions ranging from 100 bps to ~10,000 bps in the assembled genome relative to the international reference sequence (GRCh38). To validate and characterize these insertions, we mapped short-reads from 1070 Japanese individuals and 728 individuals from eight other populations to insertions integrated into GRCh38. With this result, we constructed JRGv1 (Japanese Reference Genome version 1) by integrating the 903 verified insertions, totaling 1,086,173 bases, shared by at least two Japanese individuals into GRCh38. We also constructed decoyJRGv1 by concatenating 3559 verified insertions, totaling 2,536,870 bases, shared by at least two Japanese individuals or by six other assemblies. This assembly improved the alignment ratio by 0.4% on average. These results demonstrate the importance of refining the reference assembly and creating a population-specific reference genome. JRGv1 and decoyJRGv1 are available at the JRG website.
3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. International-journal Peer-reviewed

Shu Tadaka, Fumiki Katsuoka, Masao Ueki, Kaname Kojima, Satoshi Makino, Sakae Saito, Akihito Otsuki, Chinatsu Gocho, Mika Sakurai-Yageta, Inaho Danjoh, Ikuko N Motoike, Yumi Yamaguchi-Kabata, Matsuyuki Shirota, Seizo Koshiba, Masao Nagasaki, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Atsushi Shimizu, Jun Yasuda, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

Human genome variation　6　28-28　2019

DOI： 10.1038/s41439-019-0059-5 　

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The first step towards realizing personalized healthcare is to catalog the genetic variations in a population. Since the dissemination of individual-level genomic information is strictly controlled, it will be useful to construct population-level allele frequency panels with easy-to-use interfaces. In the Tohoku Medical Megabank Project, we sequenced nearly 4000 individuals from a Japanese population and constructed an allele frequency panel of 3552 individuals after removing related samples. The panel is called the 3.5KJPNv2. It was constructed by using a standard pipeline including the 1KGP and gnomAD algorithms to reduce technical biases and to allow comparisons to other populations. Our database is the first large-scale panel providing the frequencies of variants present on the X chromosome and on the mitochondria in the Japanese population. All the data are available on our original database at https://jmorp.megabank.tohoku.ac.jp.
O-GlcNAcylation Signal Mediates Proteasome Inhibitor Resistance in Cancer Cells by Stabilizing NRF1. International-journal Peer-reviewed

Hiroki Sekine, Keito Okazaki, Koichiro Kato, M Morshedul Alam, Hiroki Shima, Fumiki Katsuoka, Tadayuki Tsujita, Norio Suzuki, Akira Kobayashi, Kazuhiko Igarashi, Masayuki Yamamoto, Hozumi Motohashi

Molecular and cellular biology　38　(17)　2018/09/01

DOI： 10.1128/MCB.00252-18 　

ISSN： 0270-7306

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Cancer cells often heavily depend on the ubiquitin-proteasome system (UPS) for their growth and survival. Irrespective of their strong dependence on the proteasome activity, cancer cells, except for multiple myeloma, are mostly resistant to proteasome inhibitors. A major cause of this resistance is the proteasome bounce-back response mediated by NRF1, a transcription factor that coordinately activates proteasome subunit genes. To identify new targets for efficient suppression of UPS, we explored, using immunoprecipitation and mass spectrometry, the possible existence of nuclear proteins that cooperate with NRF1 and identified O-linked N-acetylglucosamine transferase (OGT) and host cell factor C1 (HCF-1) as two proteins capable of forming a complex with NRF1. O-GlcNAcylation catalyzed by OGT was essential for NRF1 stabilization and consequent upregulation of proteasome subunit genes. Meta-analysis of breast and colorectal cancers revealed positive correlations in the relative protein abundance of OGT and proteasome subunits. OGT inhibition was effective at sensitizing cancer cells to a proteasome inhibitor both in culture cells and a xenograft mouse model. Since active O-GlcNAcylation is a feature of cancer metabolism, our study has clarified a novel linkage between cancer metabolism and UPS function and added a new regulatory axis to the regulation of the proteasome activity.
Regional genetic differences among Japanese populations and performance of genotype imputation using whole-genome reference panel of the Tohoku Medical Megabank Project. International-journal Peer-reviewed

Jun Yasuda, Fumiki Katsuoka, Inaho Danjoh, Yosuke Kawai, Kaname Kojima, Masao Nagasaki, Sakae Saito, Yumi Yamaguchi-Kabata, Shu Tadaka, Ikuko N Motoike, Kazuki Kumada, Mika Sakurai-Yageta, Osamu Tanabe, Nobuo Fuse, Gen Tamiya, Koichiro Higasa, Fumihiko Matsuda, Nobufumi Yasuda, Motoki Iwasaki, Makoto Sasaki, Atsushi Shimizu, Kengo Kinoshita, Masayuki Yamamoto

BMC genomics　19　(1)　551-551　2018/07/24

DOI： 10.1186/s12864-018-4942-0 　

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BACKGROUND: Genotype imputation from single-nucleotide polymorphism (SNP) genotype data using a haplotype reference panel consisting of thousands of unrelated individuals from populations of interest can help to identify strongly associated variants in genome-wide association studies. The Tohoku Medical Megabank (TMM) project was established to support the development of precision medicine, together with the whole-genome sequencing of 1070 human genomes from individuals in the Miyagi region (Northeast Japan) and the construction of the 1070 Japanese genome reference panel (1KJPN). Here, we investigated the performance of 1KJPN for genotype imputation of Japanese samples not included in the TMM project and compared it with other population reference panels. RESULTS: We found that the 1KJPN population was more similar to other Japanese populations, Nagahama (south-central Japan) and Aki (Shikoku Island), than to East Asian populations in the 1000 Genomes Project other than JPT, suggesting that the large-scale collection (more than 1000) of Japanese genomes from the Miyagi region covered many of the genetic variations of Japanese in mainland Japan. Moreover, 1KJPN outperformed the phase 3 reference panel of the 1000 Genomes Project (1KGPp3) for Japanese samples, and IKJPN showed similar imputation rates for the TMM and other Japanese samples for SNPs with minor allele frequencies (MAFs) higher than 1%. CONCLUSIONS: 1KJPN covered most of the variants found in the samples from areas of the Japanese mainland outside the Miyagi region, implying 1KJPN is representative of the Japanese population's genomes. 1KJPN and successive reference panels are useful genome reference panels for the mainland Japanese population. Importantly, the addition of whole genome sequences not included in the 1KJPN panel improved imputation efficiencies for SNPs with MAFs under 1% for samples from most regions of the Japanese archipelago.
Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. International-journal Peer-reviewed

Seizo Koshiba, Ikuko Motoike, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Yasutake Katoh, Fumiki Katsuoka, Inaho Danjoh, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Soichi Ogishima, Nobuo Fuse, Shigeo Kure, Gen Tamiya, Osamu Tanabe, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　23　(6)　406-417　2018/06

DOI： 10.1111/gtc.12588 　

ISSN： 1356-9597

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Population-based prospective cohort studies are indispensable for modern medical research as they provide important knowledge on the influences of many kinds of genetic and environmental factors on the cause of disease. Although traditional cohort studies are mainly conducted using questionnaires and physical examinations, modern cohort studies incorporate omics and genomic approaches to obtain comprehensive physical information, including genetic information. Here, we report the design and midterm results of multi-omics analysis on population-based prospective cohort studies from the Tohoku Medical Megabank (TMM) Project. We have incorporated genomic and metabolomic studies in the TMM cohort study as both metabolome and genome analyses are suitable for high-throughput analysis of large-scale cohort samples. Moreover, an association study between the metabolome and genome show that metabolites are an important intermediate phenotype connecting genetic and lifestyle factors to physical and pathologic phenotypes. We apply our metabolome and genome analyses to large-scale cohort samples in the following studies.
Identification of somatic mutations in postmortem human brains by whole genome sequencing and their implications for psychiatric disorders. International-journal Peer-reviewed

Masaki Nishioka, Miki Bundo, Junko Ueda, Fumiki Katsuoka, Yukuto Sato, Yoko Kuroki, Takao Ishii, Wataru Ukai, Shigeo Murayama, Eri Hashimoto, Masao Nagasaki, Jun Yasuda, Kiyoto Kasai, Tadafumi Kato, Kazuya Iwamoto

Psychiatry and clinical neurosciences　72　(4)　280-294　2018/04

DOI： 10.1111/pcn.12632 　

ISSN： 1323-1316

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AIM: Somatic mutations in the human brain are hypothesized to contribute to the functional diversity of brain cells as well as the pathophysiology of neuropsychiatric diseases. However, there are still few reports on somatic mutations in non-neoplastic human brain tissues. This study attempted to unveil the landscape of somatic mutations in the human brain. METHODS: We explored the landscape of somatic mutations in human brain tissues derived from three individuals with no neuropsychiatric diseases by whole-genome deep sequencing at a depth of around 100. The candidate mutations underwent multi-layered filtering, and were validated by ultra-deep target amplicon sequencing at a depth of around 200 000. RESULTS: Thirty-one somatic mutations were identified in the human brain, demonstrating the utility of whole-genome sequencing of bulk brain tissue. The mutations were enriched in neuron-expressed genes, and two-thirds of the identified somatic single nucleotide variants in the brain tissues were cytosine-to-thymine transitions, half of which were in CpG dinucleotides. CONCLUSION: Our developed filtering and validation approaches will be useful to identify somatic mutations in the human brain. The vulnerability of neuron-expressed genes to mutational events suggests their potential relevance to neuropsychiatric diseases.
Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing. International-journal Peer-reviewed

Yusuke Shibuya, Hideki Tokunaga, Sakae Saito, Kazurou Shimokawa, Fumiki Katsuoka, Li Bin, Kaname Kojima, Masao Nagasaki, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda

Genes, chromosomes & cancer　57　(2)　51-60　2018/02

DOI： 10.1002/gcc.22507 　

ISSN： 1045-2257

eISSN： 1098-2264
Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. International-journal Peer-reviewed

Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

Journal of human genetics　63　(2)　213-230　2018/02

DOI： 10.1038/s10038-017-0347-1 　

ISSN： 1434-5161

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Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.
妊娠高血圧症候群の原因解明を目指した長鎖型シークエンサーによるHLA-G遺伝子解析技術の開発

西澤絢子, 熊田和貴, 舘野恵子, 和形麻衣子, 勝岡史城, 山本雅之, 菅原準一, 安田純

生命科学系学会合同年次大会　2017年度　[2P-1139]　2017/12
Publisher: 生命科学系学会合同年次大会運営事務局
GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis. International-journal Peer-reviewed

Saori Katayama, Mikiko Suzuki, Ayaka Yamaoka, Nadine Keleku-Lukwete, Fumiki Katsuoka, Akihito Otsuki, Shigeo Kure, James Douglas Engel, Masayuki Yamamoto

Blood　130　(7)　908-919　2017/08/17

DOI： 10.1182/blood-2016-12-756767 　

ISSN： 0006-4971

eISSN： 1528-0020
A Histologic Categorization of Aqueous Outflow Routes in Familial Open-Angle Glaucoma and Associations With Mutations in the MYOC Gene in Japanese Patients. International-journal Peer-reviewed

Teruhiko Hamanaka, Masae Kimura, Tetsuro Sakurai, Nobuo Ishida, Jun Yasuda, Masao Nagasaki, Naoki Nariai, Atsushi Endo, Kei Homma, Fumiki Katsuoka, Yoichi Matsubara, Masayuki Yamamoto, Nobuo Fuse

Investigative ophthalmology & visual science　58　(5)　2818-2831　2017/05/01

DOI： 10.1167/iovs.16-20646 　

ISSN： 0146-0404

eISSN： 1552-5783
Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis. International-journal Peer-reviewed

Lei Yu, Jun Takai, Akihito Otsuki, Fumiki Katsuoka, Mikiko Suzuki, Saori Katayama, Masahiro Nezu, James Douglas Engel, Takashi Moriguchi, Masayuki Yamamoto

Molecular and cellular biology　37　(8)　2017/04/15

DOI： 10.1128/MCB.00592-16 　

ISSN： 0270-7306

eISSN： 1098-5549
Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation. International-journal Peer-reviewed

Kouhei Tsuchida, Tadayuki Tsujita, Makiko Hayashi, Asaka Ojima, Nadine Keleku-Lukwete, Fumiki Katsuoka, Akihito Otsuki, Haruhisa Kikuchi, Yoshiteru Oshima, Mikiko Suzuki, Masayuki Yamamoto

Free radical biology & medicine　103　236-247　2017/02

DOI： 10.1016/j.freeradbiomed.2016.12.041 　

ISSN： 0891-5849

eISSN： 1873-4596
Monitoring of minimal residual disease in early T-cell precursor acute lymphoblastic leukaemia by next-generation sequencing. International-journal Peer-reviewed

Xiaoqing Pan, Naoki Nariai, Noriko Fukuhara, Sakae Saito, Yukuto Sato, Fumiki Katsuoka, Kaname Kojima, Yoko Kuroki, Inaho Danjoh, Rumiko Saito, Shin Hasegawa, Yoko Okitsu, Aiko Kondo, Yasushi Onishi, Fuji Nagami, Hideyasu Kiyomoto, Atsushi Hozawa, Nobuo Fuse, Masao Nagasaki, Ritsuko Shimizu, Jun Yasuda, Hideo Harigae, Masayuki Yamamoto

British journal of haematology　176　(2)　318-321　2017/01

DOI： 10.1111/bjh.13948 　

ISSN： 0007-1048

eISSN： 1365-2141
Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies. International-journal Peer-reviewed

Tsuyoshi Hachiya, Ryohei Furukawa, Yuh Shiwa, Hideki Ohmomo, Kanako Ono, Fumiki Katsuoka, Masao Nagasaki, Jun Yasuda, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Kozo Tanno, Mamoru Satoh, Ryujin Endo, Makoto Sasaki, Kiyomi Sakata, Seiichiro Kobayashi, Kuniaki Ogasawara, Jiro Hitomi, Kenji Sobue, Atsushi Shimizu

NPJ genomic medicine　2　11-11　2017

DOI： 10.1038/s41525-017-0016-5 　

ISSN： 2056-7944
The structural origin of metabolic quantitative diversity. International-journal Peer-reviewed

Seizo Koshiba, Ikuko Motoike, Kaname Kojima, Takanori Hasegawa, Matsuyuki Shirota, Tomo Saito, Daisuke Saigusa, Inaho Danjoh, Fumiki Katsuoka, Soichi Ogishima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Miyuki Sakurai, Sachiko Hirano, Junichi Nakata, Hozumi Motohashi, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Yoichi Suzuki, Shigeo Kure, Nobuo Yaegashi, Osamu Tanabe, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

Scientific reports　6　31463-31463　2016/08/16

DOI： 10.1038/srep31463 　

ISSN： 2045-2322
Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism. International-journal Peer-reviewed

Akira Uruno, Yoko Yagishita, Fumiki Katsuoka, Yasuo Kitajima, Aki Nunomiya, Ryoichi Nagatomi, Jingbo Pi, Shyam S Biswal, Masayuki Yamamoto

Molecular and cellular biology　36　(11)　1655-72　2016/06/01

DOI： 10.1128/MCB.01095-15 　

ISSN： 0270-7306

eISSN： 1098-5549
Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection. International-journal Peer-reviewed

Akihito Otsuki, Mikiko Suzuki, Fumiki Katsuoka, Kouhei Tsuchida, Hiromi Suda, Masanobu Morita, Ritsuko Shimizu, Masayuki Yamamoto

Free radical biology & medicine　91　45-57　2016/02

DOI： 10.1016/j.freeradbiomed.2015.12.005 　

ISSN： 0891-5849

eISSN： 1873-4596
Whole-genome Japanese Reference Panel and future directions Peer-reviewed

Nagasaki Masao, Yasuda Jun, Katsuoka Fumiki, Nariai Naoki, Kojima Kaname, Kawai Yosuke, Yamaguchi-Kabata Yumi, Yokozawa Junji, Danjoh Inaho, Saito Sakae, Sato Yukuto, Mimori Takahiro, Tsuda Kaoru, Saito Rumiko, Pan Xiaoqing, Nishikawa Satoshi, Ito Shin, Kuroki Yoko, Tanabe Osamu, Fuse Nobuo, Kuriyama Shinichi, Kiyomoto Hideyasu, Hozawa Atsushi, Minegishi Naoko, Kinoshita Kengo, Kure Shigeo, Yaegashi Nobuo, Yamamoto Masayuki

GENES & GENETIC SYSTEMS　90　(6)　377　2015/12

ISSN： 1341-7568
Discovery of an NRF1-specific inducer from a large-scale chemical library using a direct NRF1-protein monitoring system. International-journal Peer-reviewed

Tadayuki Tsujita, Liam Baird, Yuki Furusawa, Fumiki Katsuoka, Yoshika Hou, Satomi Gotoh, Shin-ichi Kawaguchi, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　20　(7)　563-77　2015/07

DOI： 10.1111/gtc.12248 　

ISSN： 1356-9597

eISSN： 1365-2443
Molecular basis distinguishing the DNA binding profile of Nrf2-Maf heterodimer from that of Maf homodimer.

Momoko Kimura, Tae Yamamoto, Jianyong Zhang, Ken Itoh, Motoki Kyo, Terue Kamiya, Hiroyuki Aburatani, Fumiki Katsuoka, Hirofumi Kurokawa, Toshiyuki Tanaka, Hozumi Motohashi, Masayuki Yamamoto

Journal of Biological Chemistry　290　(17)　10644-10644　2015/04
Publisher: Elsevier BV
DOI： 10.1074/jbc.a115.706863 　

ISSN： 0021-9258
DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway. International-journal Peer-reviewed

Keizo Nishikawa, Yoriko Iwamoto, Yasuhiro Kobayashi, Fumiki Katsuoka, Shin-ichi Kawaguchi, Tadayuki Tsujita, Takashi Nakamura, Shigeaki Kato, Masayuki Yamamoto, Hiroshi Takayanagi, Masaru Ishii

Nature medicine　21　(3)　281-7　2015/03

DOI： 10.1038/nm.3774 　

ISSN： 1078-8956

eISSN： 1546-170X
iJGVD: an integrative Japanese genome variation database based on whole-genome sequencing. International-journal Peer-reviewed

Yumi Yamaguchi-Kabata, Naoki Nariai, Yosuke Kawai, Yukuto Sato, Kaname Kojima, Minoru Tateno, Fumiki Katsuoka, Jun Yasuda, Masayuki Yamamoto, Masao Nagasaki

Human genome variation　2　15050-15050　2015

DOI： 10.1038/hgv.2015.50 　

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The integrative Japanese Genome Variation Database (iJGVD; http://ijgvd.megabank.tohoku.ac.jp/) provides genomic variation data detected by whole-genome sequencing (WGS) of Japanese individuals. Specifically, the database contains variants detected by WGS of 1,070 individuals who participated in a genome cohort study of the Tohoku Medical Megabank Project. In the first release, iJGVD includes >4,300,000 autosomal single nucleotide variants (SNVs) whose minor allele frequencies are >5.0%.
An efficient quantitation method of next-generation sequencing libraries by using MiSeq sequencer. International-journal Peer-reviewed

Fumiki Katsuoka, Junji Yokozawa, Kaoru Tsuda, Shin Ito, Xiaoqing Pan, Masao Nagasaki, Jun Yasuda, Masayuki Yamamoto

Analytical biochemistry　466　27-9　2014/12/01

DOI： 10.1016/j.ab.2014.08.015 　

ISSN： 0003-2697

eISSN： 1096-0309
Validation of multiple single nucleotide variation calls by additional exome analysis with a semiconductor sequencer to supplement data of whole-genome sequencing of a human population. International-journal Peer-reviewed

Ikuko N Motoike, Mitsuyo Matsumoto, Inaho Danjoh, Fumiki Katsuoka, Kaname Kojima, Naoki Nariai, Yukuto Sato, Yumi Yamaguchi-Kabata, Shin Ito, Hisaaki Kudo, Ichiko Nishijima, Satoshi Nishikawa, Xiaoqing Pan, Rumiko Saito, Sakae Saito, Tomo Saito, Matsuyuki Shirota, Kaoru Tsuda, Junji Yokozawa, Kazuhiko Igarashi, Naoko Minegishi, Osamu Tanabe, Nobuo Fuse, Masao Nagasaki, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

BMC genomics　15　673-673　2014/08/10

DOI： 10.1186/1471-2164-15-673 　

ISSN： 1471-2164
Transcription factor NF-E2-related factor 1 impairs glucose metabolism in mice. International-journal Peer-reviewed

Yosuke Hirotsu, Chika Higashi, Toshiaki Fukutomi, Fumiki Katsuoka, Tadayuki Tsujita, Yoko Yagishita, Yuka Matsuyama, Hozumi Motohashi, Akira Uruno, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　19　(8)　650-65　2014/08

DOI： 10.1111/gtc.12165 　

ISSN： 1356-9597

eISSN： 1365-2443
Nrf2 deficiency leads to behavioral, neurochemical and transcriptional changes in mice. International-journal Peer-reviewed

Hiroyuki Muramatsu, Fumiki Katsuoka, Katsuo Toide, Yusuke Shimizu, Shoji Furusako, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　18　(10)　899-908　2013/10

DOI： 10.1111/gtc.12083 　

ISSN： 1356-9597
Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. International-journal Peer-reviewed

Yosuke Hirotsu, Fumiki Katsuoka, Ryo Funayama, Takeshi Nagashima, Yuichiro Nishida, Keiko Nakayama, James Douglas Engel, Masayuki Yamamoto

Nucleic acids research　40　(20)　10228-39　2012/11/01

DOI： 10.1093/nar/gks827 　

ISSN： 0305-1048

eISSN： 1362-4962
Embryonic lethality and fetal liver apoptosis in mice lacking all three small Maf proteins. International-journal Peer-reviewed

Hiromi Yamazaki, Fumiki Katsuoka, Hozumi Motohashi, James Douglas Engel, Masayuki Yamamoto

Molecular and cellular biology　32　(4)　808-16　2012/02

DOI： 10.1128/MCB.06543-11 　

ISSN： 0270-7306
Central nervous system-specific deletion of transcription factor Nrf1 causes progressive motor neuronal dysfunction. International-journal Peer-reviewed

Akira Kobayashi, Takako Tsukide, Tomohiro Miyasaka, Tomoko Morita, Tatsuya Mizoroki, Yoshiro Saito, Yasuo Ihara, Akihiko Takashima, Noriko Noguchi, Akiyoshi Fukamizu, Yosuke Hirotsu, Makiko Ohtsuji, Fumiki Katsuoka, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　16　(6)　692-703　2011/06

DOI： 10.1111/j.1365-2443.2011.01522.x 　

ISSN： 1356-9597
Nrf2 degron-fused reporter system: a new tool for specific evaluation of Nrf2 inducers. International-journal Peer-reviewed

Yosuke Hirotsu, Fumiki Katsuoka, Ken Itoh, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　16　(4)　406-15　2011/04

DOI： 10.1111/j.1365-2443.2011.01496.x 　

ISSN： 1356-9597
Molecular determinants for small Maf protein control of platelet production. International-journal Peer-reviewed

Hozumi Motohashi, Rie Fujita, Mariko Takayama, Ai Inoue, Fumiki Katsuoka, Emery H Bresnick, Masayuki Yamamoto

Molecular and cellular biology　31　(1)　151-62　2011/01

DOI： 10.1128/MCB.00798-10 　

ISSN： 0270-7306
NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation. International-journal Peer-reviewed

Hozumi Motohashi, Momoko Kimura, Rie Fujita, Ai Inoue, Xiaoqing Pan, Mariko Takayama, Fumiki Katsuoka, Hiroyuki Aburatani, Emery H Bresnick, Masayuki Yamamoto

Blood　115　(3)　677-86　2010/01/21

DOI： 10.1182/blood-2009-05-223107 　

ISSN： 0006-4971
Hepatocyte-specific deletion of heme oxygenase-1 disrupts redox homeostasis in basal and oxidative environments. Peer-reviewed

Takashi Mamiya, Fumiki Katsuoka, Aki Hirayama, Osamu Nakajima, Akira Kobayashi, Jonathan M Maher, Hirofumi Matsui, Ichinosuke Hyodo, Masayuki Yamamoto, Tomonori Hosoya

The Tohoku journal of experimental medicine　216　(4)　331-9　2008/12

DOI： 10.1620/tjem.216.331 　

ISSN： 0040-8727

eISSN： 1349-3329
Nrf1 and Nrf2 play distinct roles in activation of antioxidant response element-dependent genes. International-journal Peer-reviewed

Makiko Ohtsuji, Fumiki Katsuoka, Akira Kobayashi, Hiroyuki Aburatani, John D Hayes, Masayuki Yamamoto

The Journal of biological chemistry　283　(48)　33554-62　2008/11/28

DOI： 10.1074/jbc.M804597200 　

ISSN： 0021-9258
Molecular basis distinguishing the DNA binding profile of Nrf2-Maf heterodimer from that of Maf homodimer. International-journal Peer-reviewed

Momoko Kimura, Tae Yamamoto, Jianyong Zhang, Ken Itoh, Motoki Kyo, Terue Kamiya, Hiroyuki Aburatani, Fumiki Katsuoka, Hirofumi Kurokawa, Toshiyuki Tanaka, Hozumi Motohashi, Masayuki Yamamoto

The Journal of biological chemistry　282　(46)　33681-33690　2007/11/16

DOI： 10.1074/jbc.M706863200 　

ISSN： 0021-9258
Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. International-journal Peer-reviewed

Melinda S Yates, Masafumi Tauchi, Fumiki Katsuoka, Kathleen C Flanders, Karen T Liby, Tadashi Honda, Gordon W Gribble, Delinda A Johnson, Jeffrey A Johnson, Neal C Burton, Tomás R Guilarte, Masayuki Yamamoto, Michael B Sporn, Thomas W Kensler

Molecular cancer therapeutics　6　(1)　154-62　2007/01

DOI： 10.1158/1535-7163.MCT-06-0516 　

ISSN： 1535-7163
Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism Peer-reviewed

Kit I. Tong, Akira Kobayashi, Fumiki Katsuoka, Masayuki Yamamoto

BIOLOGICAL CHEMISTRY　387　(10-11)　1311-1320　2006/10

DOI： 10.1515/BC.2006.164 　

ISSN： 1431-6730
MafG sumoylation is required for active transcriptional repression. International-journal Peer-reviewed

Hozumi Motohashi, Fumiki Katsuoka, Chika Miyoshi, Yasuhiro Uchimura, Hisato Saitoh, Claire Francastel, James Douglas Engel, Masayuki Yamamoto

Molecular and cellular biology　26　(12)　4652-63　2006/06

DOI： 10.1128/MCB.02193-05 　

ISSN： 0270-7306

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A straightforward mechanism for eliciting transcriptional repression would be to simply block the DNA binding site for activators. Such passive repression is often mediated by transcription factors that lack an intrinsic repressor activity. MafG is a bidirectional regulator of transcription, a repressor in its homodimeric state but an activator when heterodimerized with p45. Here, we report that MafG is conjugated to SUMO-2/3 in vivo. To clarify the possible physiological role(s) for sumoylation in regulating MafG activity, we evaluated mutant and wild-type MafG in transgenic mice and cultured cells. Whereas sumoylation-deficient MafG activated p45-dependent transcription normally and did not affect heterodimer activity, repression by the sumoylation-deficient MafG mutant was severely compromised in vivo. Furthermore, the SUMO-dependent repression activity of MafG was sensitive to histone deacetylase inhibition. Thus, repression by MafG is not achieved through simple passive repression by competing for the activator binding site but requires sumoylation, which then mediates transcriptional repression through recruitment of a repressor complex containing histone deacetylase activity.
Players regulating and supporting cytoprotective function of Nrf2 Peer-reviewed

Hozumi Motohashi, Takafumi Suzuki, Hiromi Okawa, Kit Tong, Fumiki Katsuoka, Akira Kobayashi, Masayuki Yamamoto

DRUG METABOLISM REVIEWS　38　22-22　2006

ISSN： 0360-2532
Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions. International-journal Peer-reviewed

Masafumi Tauchi, Azumi Hida, Takaaki Negishi, Fumiki Katsuoka, Shuhei Noda, Junsei Mimura, Tomonori Hosoya, Akinori Yanaka, Hiroyuki Aburatani, Yoshiaki Fujii-Kuriyama, Hozumi Motohashi, Masayuki Yamamoto

Molecular and cellular biology　25　(21)　9360-8　2005/11

DOI： 10.1128/MCB.25.21.9360-9368.2005 　

ISSN： 0270-7306
Genetic evidence that small maf proteins are essential for the activation of antioxidant response element-dependent genes. International-journal Peer-reviewed

Fumiki Katsuoka, Hozumi Motohashi, Tetsuro Ishii, Hiroyuki Aburatani, James Douglas Engel, Masayuki Yamamoto

Molecular and cellular biology　25　(18)　8044-51　2005/09

DOI： 10.1128/MCB.25.18.8044-8051.2005 　

ISSN： 0270-7306
Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment. International-journal Peer-reviewed

Tsutomu Toki, Fumiki Katsuoka, Rika Kanezaki, Gang Xu, Hidekachi Kurotaki, Jiying Sun, Takuya Kamio, Seiji Watanabe, Satoru Tandai, Kiminori Terui, Soroku Yagihashi, Norio Komatsu, Kazuhiko Igarashi, Masayuki Yamamoto, Etsuro Ito

Blood　105　(8)　3100-8　2005/04/15

DOI： 10.1182/blood-2004-07-2826 　

ISSN： 0006-4971
Nrf2 transcriptionally activates the mafG gene through an antioxidant response element. International-journal Peer-reviewed

Fumiki Katsuoka, Hozumi Motohashi, James Douglas Engel, Masayuki Yamamoto

The Journal of biological chemistry　280　(6)　4483-90　2005/02/11

DOI： 10.1074/jbc.M411451200 　

ISSN： 0021-9258
Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. International-journal Peer-reviewed

Hozumi Motohashi, Fumiki Katsuoka, James Douglas Engel, Masayuki Yamamoto

Proceedings of the National Academy of Sciences of the United States of America　101　(17)　6379-84　2004/04/27

DOI： 10.1073/pnas.0305902101 　

ISSN： 0027-8424
The dred repressor. Peer-reviewed

Tanabe O, Katsuoka F, Campbell A, Kobayashi S, Yamamoto M, Tanimoto K, Engel D

BLOOD CELLS MOLECULES AND DISEASES　31　(1)　139　2003/07

ISSN： 1079-9796
Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response. International-journal Peer-reviewed

Fumiki Katsuoka, Hozumi Motohashi, Yuna Tamagawa, Shigeo Kure, Kazuhiko Igarashi, James Douglas Engel, Masayuki Yamamoto

Molecular and cellular biology　23　(4)　1163-74　2003/02

DOI： 10.1128/MCB.23.4.1163-1174.2003 　

ISSN： 0270-7306

eISSN： 1098-5549
Transgenic expression of BACH1 results in megakaryocytic linage impairement. Peer-reviewed

T Toki, F Katsuoka, R Kanezaki, T Kamio, S Tandai, H Kurotaki, S Yagihashi, K Igarashi, M Yamamoto, E Ito

BLOOD　100　(11)　721A-721A　2002/11

ISSN： 0006-4971
Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. International-journal Peer-reviewed

Hozumi Motohashi, Tania O'Connor, Fumiki Katsuoka, James Douglas Engel, Masayuki Yamamoto

Gene　294　(1-2)　1-12　2002/07/10

DOI： 10.1016/S0378-1119(02)00788-6 　

ISSN： 0378-1119
An embryonic/fetal beta-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer. International-journal Peer-reviewed

Osamu Tanabe, Fumiki Katsuoka, Andrew D Campbell, Weimin Song, Masayuki Yamamoto, Keiji Tanimoto, James Douglas Engel

The EMBO journal　21　(13)　3434-42　2002/07/01

DOI： 10.1093/emboj/cdf340 　

ISSN： 0261-4189
Solution structure of the DNA-binding domain of MafG. International-journal Peer-reviewed

Hideki Kusunoki, Hozumi Motohashi, Fumiki Katsuoka, Akio Morohashi, Masayuki Yamamoto, Toshiyuki Tanaka

Nature structural biology　9　(4)　252-6　2002/04

DOI： 10.1038/nsb771 　

ISSN： 1072-8368
Positive or negative MARE-dependent transcriptional regulation is by the abundance of small Maf proteins Peer-reviewed

H Motohashi, F Katsuoka, JA Shavit, JD Engel, M Yamamoto

CELL　103　(6)　865-875　2000/12

DOI： 10.1016/S0092-8674(00)00190-2 　

ISSN： 0092-8674

eISSN： 1097-4172
Functional characterization of the two alternative promoters of human p45 NF-E2 gene Peer-reviewed

T Toki, K Arai, K Terui, N Komatsu, M Yokoyama, F Katsuoka, M Yamamoto, E Ito

EXPERIMENTAL HEMATOLOGY　28　(10)　1113-1119　2000/10

DOI： 10.1016/S0301-472X(00)00523-3 　

ISSN： 0301-472X
One enhancer mediates mafK transcriptional activation in both hematopoietic and cardiac muscle cells Peer-reviewed

F Katsuoka, H Motohashi, K Onodera, N Suwabe, JD Engel, M Yamamoto

EMBO JOURNAL　19　(12)　2980-2991　2000/06

DOI： 10.1093/emboj/19.12.2980 　

ISSN： 0261-4189

eISSN： 1460-2075
Characterization of the murine mafF gene Peer-reviewed

K Onodera, JA Shavit, H Motohashi, F Katsuoka, JE Akasaka, JD Engel, M Yamamoto

JOURNAL OF BIOLOGICAL CHEMISTRY　274　(30)　21162-21169　1999/07

DOI： 10.1074/jbc.274.30.21162 　

ISSN： 0021-9258
Type II alveolar epithelial cells in lung express receptor for advanced glycation end products (RAGE) gene Peer-reviewed

F Katsuoka, Y Kawakami, T Arai, H Imuta, M Fujiwara, H Kanma, K Yamashita

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　238　(2)　512-516　1997/09

DOI： 10.1006/bbrc.1997.7263 　

ISSN： 0006-291X

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Misc. 16

集団特異的基準ゲノムの構築と日本人基準ゲノム配列 JG1

髙山順, 勝岡史城

遺伝子医学　10　(33)　2020
東北メディカル・メガバンク計画が実施するゲノムコホート研究

勝岡史城, 山本雅之

医学のあゆみ　266　(5)　370-376　2018
Keap1-Nrf2システムが担う生体防御機構 (特集活性酸素・フリーラジカル機能と病態解明への新たなる展開バイオスピンとシグナル伝達)

勝岡史城, 山本雅之

細胞工学　25　(2)　153-156　2006/02
Publisher: 秀潤社
ISSN： 0287-3796
重症喘息患者を対象とした全血網羅的遺伝子発現解析;好中球活性化の関与

鈴木眞奈美, 山田充啓, 藤野直也, 吉良聡, 笠澄望, 元池育子, 元池育子, 上出庸介, 関谷潔史, 小林誠一, 佐藤輝幸, 松本周一郎, 小野祥直, 今野周一, 遠藤卓人, 玉田勉, 谷口正実, 勝岡史城, 木下賢吾, 杉浦久敏

アレルギー　73　(6/7)　2024

ISSN： 0021-4884
長鎖リードシークエンス技術を用いた日本人構造多型パネルJSV1の構築

大槻晃史, 大槻晃史, 岡村容伸, 岡村容伸, 勝岡史城, 勝岡史城, 木下賢吾, 木下賢吾, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之, 山本雅之

日本生化学会大会(Web)　95th　2022
本邦における鉄代謝異常に伴う貧血に関する包括的疫学研究

藤原亨, 大根田絹子, 佐々木克幸, 青木裕一, 工藤久智, 勝岡史城, 熊田和貴, 萩島創一, 山本雅之, 張替秀郎, 張替秀郎

日本鉄バイオサイエンス学会学術集会プログラム・抄録集　46th　2022
Exploration of BRCA1/2 gene variants in a general population cohort and return of genomic results to the participants

徳永英樹, 安田純, 島田宗昭, 濱中洋平, 重田昌吾, 布施昇男, 勝岡史城, 荻島創一, 荻島創一, 山口由美, 寳澤篤, 川目裕, 大根田絹子, 青木洋子, 山本雅之, 八重樫伸生

日本癌学会学術総会抄録集(Web)　81st　2022
多層オミックス解析による認知症の早期発見のためのバイオマーカー探索

多田羅洋太, 中村智洋, 山嵜博未, 勝岡史城, 千葉満, 三枝大輔, 葛西秋宅, 伊東健

JSBMS Letters　45　(Suppl.)　32-32　2020/08
Publisher: (一社)日本医用マススペクトル学会
ISSN： 1881-5464
早発型発達緑内障における原因遺伝子の探索

布施昇男, 木村雅恵, 清水愛, 河合洋介, 小島要, 長崎正朗, 濱中輝彦, 石田誠夫, 中村誠, 酒井寛, 池田陽子, 森和彦, 中澤徹, 勝岡史城, 安田純, 山本雅之

日本眼科学会雑誌　121　(臨増)　227-227　2017/03
Publisher: (公財)日本眼科学会
ISSN： 0029-0203
マルチオミクスが解き明かす疾患生物学日本人多層オミックス参照パネルの拡張

小柴生造, 三枝大輔, 元池育子, 小島要, 城田松之, 齋藤智, 勝岡史城, 河合洋介, 山口由美, 田邉修, 長崎正郎, 安田純, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　89回　[1S05-5]　2016/09
Publisher: (公社)日本生化学会
眼疾患と遺伝子緑内障のゲノム解析次世代医療・個別化医療に向けて

布施昇男, 清水愛, 木村雅恵, 高野良真, 石棟, 宮澤晃子, 国松志保, 劉孟林, 渡邉亮, 安田正幸, 横山悠, 檜森紀子, 津田聡, 山本耕太郎, 中澤徹, 安田純, 勝岡史城, 小島要, 成相直樹, 松本光代, 元池育子, 長崎正朗, 木下賢吾, 五十嵐和彦, 山本雅之, 新堀哲也, 青木洋子, 松原洋一, 舟山亮, 長嶋剛史, 中山啓子, 眞島行彦, 船山智代, 田中光一, 原田高幸, 阿部春樹, 福地健郎, 安田典子, 出田秀尚, 鄭暁東, 白石敦, 大橋裕一, 石田誠夫, 原岳, 金森章泰, 山田裕子, 中村誠, 酒井寛, Richards Julia E

日本眼科学会雑誌　118　(3)　216-240　2014/03
Publisher: (公財)日本眼科学会
ISSN： 0029-0203
Integrated mechanisms for detoxification and anti-oxidant response in animals

H Motohashi, T Suzuki, H Okawa, K Tong, M Tauchi, F Katsuoka, A Kobayashi, Y Fujii, M Yamamoto

PLANT AND CELL PHYSIOLOGY　47　S19-S19　2006

ISSN： 0032-0781
Identification of a novel functional domain conferring positive and negative bidirectional regulator property on MafG in megakaryocytes.

H Motohashi, F Katsuoka, C Francastel, JD Engel, M Yamamoto

BLOOD CELLS MOLECULES AND DISEASES　34　(2)　107-108　2005/03

ISSN： 1079-9796
Small Maf proteins are dispensable for the expression of globin genes in primitive hematopoiesis.

F Katsuoka, H Motohashi, JD Engel, M Yamamoto

BLOOD CELLS MOLECULES AND DISEASES　34　(2)　97-97　2005/03

ISSN： 1079-9796
Contribution of small maf transcription factors to erythropoiesis.

D Engel, K Igarashi, F Katsuoka, H Motohashi, K Onodera, J Shavit, N Suwabe, M Yamamato

BLOOD CELLS MOLECULES AND DISEASES　26　(5)　494-495　2000/10

ISSN： 1079-9796
Genetic switch for transcriptional activation through MARE composed of the balance between small Maf factors and their partner molecules.

H Motohashi, F Katsuoka, JD Engel, M Yamamoto

BLOOD CELLS MOLECULES AND DISEASES　26　(5)　522-522　2000/10

ISSN： 1079-9796

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Presentations 34

コホート研究から導くがんの早期診断とゲノム情報を活用した個別化予防 Invited

勝岡史城

「未病」に科学技術イノベーションをおこします！～あなたに寄りそう「サイエンス未病」～　2023/11/16
Functional Characterization of CNC-sMAF Heterodimers by the Tethered Dimer Rescue System

Fumiki KATSUOKA

The Environmental Response VI　2023/11/04
シークエンス技術の進歩が支える東北メディカル・メガバンク機構のゲノムコホート Invited

勝岡史城

第96回日本生化学会大会　2023/10/31
Nrf2-MafGヘテロ二量体の転写制御におけるMafG C末端の機能

奥山遥奈, 畑中望, 山本雅之, 勝岡史城

第95回日本生化学会大会　2022/11/11
テザード二量体が明らかにするNrf1-MafGヘテロ二量体のタンパク質恒常性ストレス応答遺伝子の発現制御に対する貢献

勝岡史城, 大槻晃史, 畑中望, 山本雅之

第94回日本生化学会大会　2021/11/04
テザード二量体を用いた機能解析が示すNrf1-MafGとNrf2-MafGヘテロ二量体の標的遺伝子選択特異性

勝岡史城, 大槻晃史, 畑中望, 山本雅之

第42回日本分子生物学会年会　2019/12/06
Nrf2-MafGテザードヘテロ二量体分子は小Maf群因子欠失細胞においてNrf2標的遺伝子の一群を特異的に活性化する

勝岡史城, 大槻晃史, 高橋瑞枝, 山本雅之

第91回日本生化学会大会　2018/09/26
酸化ストレス・異物代謝関連遺伝子の発現を制御するNrf2-小Maf群因子ヘテロ二量体

勝岡史城

INGEM&ToMMoセミナー　2019/12/12
東北メディカル・メガバンク機構が実施する15万人規模の前向きゲノムコホート

勝岡史城

東京大学新領域創成科学研究科バイオ機能情報解析学講義　2019/11/26
Oxidative stress response mediated by specific heterodimers of bZIP transcription factors

KATSUOKA Fumiki

The ToMMo-Stanford Symposium　2019/11/26
Transcriptomic profiling of stress-responsive genes on lymphoblastoid cell lines of the TMM project.

KATSUOKA Fumiki

The 5th ToMMo-NHRI Conference　2019/07/09
東北メディカル・メガバンクプロジェクトが実施するゲノムコホート研究の戦略

勝岡史城

バイオサンプルの保管と活用に関するワークショップ, 放射線影響研究所　2019/02/18
ヒトゲノムはどこまで解読できたのか

勝岡史城

生化学若い研究者の会東北支部初夏のセミナー　2018/06/16
東北メディカル・メガバンク計画によるゲノム解析データ

勝岡史城

平成29年度AMED脳と心の研究課研究交流会　2017/11/30
NGSによる全ゲノム解析を超えて

勝岡史城

NGS現場の会第五回研究会　2017/05/22
東北メディカル・メガバンク機構のゲノム解析

勝岡史城

第一回東北メディカル・メガバンク計画合同研究会　2017/01/27
肝臓特異的小Maf群因子欠失マウスは、脂肪肝を呈し、Nrf1ならびにNrf2依存的な遺伝子の発現制御不全を示す

勝岡史城, 山㟢博未, 山本雅之

第89回日本生化学会大会　2016/09/25
マルチオミクスが解き明かす疾患生物学日本人多層オミックス参照パネルの拡張

小柴生造, 三枝大輔, 元池育子, 小島要, 城田松之, 齋藤智, 勝岡史城, 河合洋介, 山口由美, 田邉修, 長崎正郎, 安田純, 木下賢吾, 山本雅之

第89会日本生化学会大会　2016/09
東北メディカル・メガバンク機構におけるイルミナシークエンサーの運用

勝岡史城

イルミナ次世代シーケンサーフォーラム2014　2014/07/16
東北メディカル・メガバンクにおけるシークエンス解析プラットフォーム

勝岡史城, 横澤潤二, 潘小青, 齋藤さかえ, 津田薫, 檀上稲穂, 齋藤るみ子, 長崎正朗, 田邉修, 布施昇男, 安田純, 山本雅之

NGS現場の会第三回研究会　2013/09/04
CNC因子と小Maf因子のヘテロ二量体による生体防御遺伝子の発現制御の意義

勝岡史城

第84回日本生化学会大会　2011/09/21
Molecular basis of CNC and small Maf dimer function in neural tissues.

KATSUOKA Fumiki

Jornada Cientifica-Regulatory mechanisms in inflammatory processes.　2010/10/15
Nrf2 is degraded by Keap1-independent proteasome pathway in the absence of small Maf proteins

勝岡史城, 中山博未, 本橋ほづみ, 山本雅之

第32回日本分子生物学会年会　2009/12/09
マウス胎生期における小Maf群因子の機能

勝岡史城, 中山博未, 本橋ほづみ, Engel JD, 山本雅之

日本生化学会東北支部第75回例会・シンポジウム　2009/05/09
小Maf群因子三重欠失細胞レスキュー系を用いた小Maf群因子の機能解析

勝岡史城, 中山博未, 本橋ほづみ, 山本雅之

第31回日本分子生物学会年会、第81回日本生化学会大会・合同大会　2008/12/09
Nrf2の核への安定局在化における小Maf群因子の重要性の検討

勝岡史城, 中山博未, 本橋ほづみ, 山本雅之

第30回日本分子生物学会年会、第80回日本生化学会大会・合同大会　2007/12
mafG::mafK複合欠失マウス巨核球で減少している新規遺伝子Clone-325の機能解析

勝岡史城, 玉川優奈, 大根田修, 西川光郎, 加藤尚志, 本橋ほづみ, 山本雅之

第28回日本分子生物学会年会　2005/12
酸化ストレス応答・異物代謝系遺伝子の発現制御に対する小Maf群因子の多様な貢献

勝岡史城, 本橋ほづみ, 石井哲郎, 山本雅之

第27回日本分子生物学会年会　2004/12
小Maf群因子複合欠失マウスにおける酸化ストレス応答・異物代謝系遺伝子の発現制御

勝岡史城, 本橋ほづみ, 石井哲郎, 山本雅之

第26回日本分子生物学会年会　2003/12
MARE配列に対する制御異常がもたらす進行性運動失調とその分子機構

勝岡史城, 本橋ほづみ, 玉川優奈, 呉繁夫, 五十嵐和彦, J.D. Engel, 山本雅之

第24回日本分子生物学会年会　2001/12
小Maf群蛋白質遺伝子欠失マウスの示す進行性の運動失調とその分子機構

勝岡史城, 本橋ほづみ, 玉川優奈, 五十嵐和彦, 山本雅之

第23回日本分子生物学会年会　2000/12
GATA因子に依存したマウスmafK遺伝子の造血細胞と心筋での発現調節機構

勝岡史城, 本橋ほづみ, 山本雅之

第72回日本生化学会大会　1999/10
マウスmafK遺伝子の造血細胞における発現制御領域の個体レベルでの同定

勝岡史城, 本橋ほづみ, 山本雅之

第21回日本分子生物学会年会　1998/12
AGEレセプター(RAGE)の発現調節因子に関する検討

勝岡史城, 川上康, 曽根博仁, 新井健夫, 河野一弥, 山下亀次郎

第39回日本糖尿病学会年次学術集会　1996/05

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Research Projects 11

ストレス応答転写制御に果たす小Maf群因子の機能とがん悪性化との関連性

勝岡史城

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 基盤研究(C)

Institution: 東北大学

2020/04/01 - 2023/03/31

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塩基性領域-ロイシンジッパー（bZIP）型転写因子であるCNC群因子と小Maf群因子（sMaf）のヘテロ二量体は、様々な生体防御遺伝子群の発現を制御する。また、CNC-sMaf二量体は、がん細胞の悪性化との関連も報告されている。ヒトを含む脊椎動物では、3種類のsMaf群因子（MafF, MafG, MafK）が同定されているが、各因子の機能の違いは充分解析されていない。本研究では、3種類のsMaf群因子の機能的な差異を明らかにすることを目的としている。研究手法としては、CNC群因子の一つNrf2とsMaf因子をリンカーペプチドで融合させたテザード分子を構築し、これをsMaf群因子の三重欠失細胞（MafF-/-:MafG-/-:MafK-/-）に導入することで、内在性のsMafを含む二量体の干渉を受けずに、導入したテザード二量体分子の機能を特異的に評価する手法（Tethered Dimer Rescue系）を用いる。令和3年度は、昨年度樹立したMafGのC末領域を欠失させたMafGΔCとNrf2のテザード分子（T-N2ΔC）の安定発現細胞株のRNAシークエンス等による機能解析を更に進めた。また、より信頼度の高いデータを得るため、テザード分子発現プラスミドのプロモーターを変更した新規のプラスミド構築を作成し、一連の機能解析を実施した。安定細胞株の樹立では、これまでのバルク培養ではなく、クローニングを実施することで、テザード分子の発現量を安定化した細胞株を樹立し、その機能解析を実施した。MafFとNrf2のテザード分子（T-N2F）のプラスミド構築も作成し、機能解析を実施した。
Preparation and Application of Y chromosome Panel using BirThree Cohort Men

Suzuki Kichiya

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2018/04/01 - 2021/03/31

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More than 10% of the causes of infertility are considered to be male factors, and genomic abnormalities are attracting attention as one of the causes. The purpose of this study was to construct a reference panel related to fertility based on the genomic basis cultivated so far. A reference panel derived from a male with fertility was created from the whole genome data held by the Tohoku Medical Megabank Organization, and the whole genome data obtained from 17 semen samples of male infertility patients was used for the subsequent analysis. However, in the end, 180K SNPs were detected, and 11K of AF>0.8 were detected. This result will be an important platform for the genome analysis of male infertility in the future.
Target gene specificity of transcription factors involved in environmental stress response

KATSUOKA FUMIKI

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Tohoku University

2017/04/01 - 2021/03/31

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In response to oxidative, xenobiotic stresses and cellular dysfunction, cells turn on a battery of cytoprotective genes to cope with them. These stress responses are regulated in part by various combinations of heterodimers composing bZIP transcription factors, CNC (Nrf1, Nrf2, Nrf3, p45 NFE2) and small Maf proteins (MafF, MafG, MafK). In this study, we established a new assay system, which allows us to analyze the function of each CNC-sMaf dimer specifically without interference from other endogenous CNC-sMaf dimers or sMaf homodimers. Using this system, together with next generation sequencing analyses, we have clearly shown that Nrf1-MafG and Nrf2-MafG heterodimers show different target gene specificity, while they bind to the same DNA sequences.
Post-translational modification of transcription factors regulates on-off switch of cell proliferation

Minegishi Naoko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Tohoku University

2015/04/01 - 2019/03/31

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GATA2 is an essential transcription factor for hematopoiesis. We analyzed the cell-cycle dependent post-translational regulation of this factor. The expression level of GATA2 and its binding to target sequences, were low in early G1 phase, then increased in G1-S transition phase. In the late S phase, GATA2 expression increased but GATA2 binding to its target sequences decreased. In M-phase, Cyclin B1-Cyclin-dependent kinase (CDK)1 phosphorylated T176 residue of GATA2, and induced the interaction with F-box/WD repeat -containing protein 7 (Fbw7) and the ubiquitin-mediated degradation of GATA2. GATA2 was also phosphorylated by Cyclin A/E-CDK2 and interacted with S-phase kinase-associated protein 2 (Skp2), which is known as a ubiquitin-conjugating enzyme of phosphorylated cyclin-dependent kinase inhibitor 1B (p27) in G1-S phase. Thus, GATA2 is under the regulation of cell-cycle specific serine/threonine phosphorylation and ubiquitin-mediated degradation.
Role of Nrf1 activation in progressive neurodegeneration

NISHIJIMA Ichiko, KATSUOKA Fumiki, AOKI Masashi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Tohoku University

2012/04/01 - 2016/03/31

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons. Although defective ubiquitin-proteasome system is associated with neurodegenerative diseases commonly, the underlying molecular mechanisms are still unknown. To understand defense mechanisms using ubiquitin-proteasome system against progressive degeneration of neurons, we have analyzed Nrf1 activation in neurodegenerative disease condition using the compound transgenic mice carrying Nrf1 and mutant human SOD1 genes. The compound transgenic mice overexpressed Nrf1 and mutant human SOD1 have similar onset of neurodegeneration to mutant SOD1 transgenic mice. However, their degenerative progression was faster than mutant SOD1 transgenic mice. Our data indicate that Nrf1 activation may contribute acceleration of neurodegenerative disorders.
Roles of stress-responsive transcription factors in health and disease

YAMAMOTO Masayuki, KATSUOKA Fumiki, URUNO Akira, SUZUKI Norio

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (A)

Institution: Tohoku University

2012/04/01 - 2015/03/31

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Transcription factor Nrf2 regulates a broad cytoprotective response to environmental stresses through induction of cellular defense enzymes. Keap1 is an adaptor protein for cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. This notion has been best demonstrated in animal models, showing that Nrf2-null mice are sensitive to a wide variety of electrophiles and reactive oxygen species (ROS). Keap1 possesses reactive cysteine residues that act as sensors for electrophilic and oxidative stresses. We have verified this model through structure biology, mouse/zebrafish genetics, and human cancer analyses. Elevated expression of NRF2 target genes confers advantages on the growth of cancer cells through the metabolic reprogramming. Thus, the Keap1-Nrf2 system opens a new avenue to the understanding of the signal transduction and regulatory processes underlying the stress response and cancer progression.
Molecular Mechanism of fatty liver in Nrf1 knockout mice

KATSUOKA Fumiki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Young Scientists (B)

Institution: Tohoku University

2011 - 2012

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Through the analyses of Nrf1 liver-specific knockout mice, we examined the function of Nrf1 in the livers. Gene expression analysis using microarray, chromatin immunoprecipitation analysis, and metabolome analysis using CE-TOFMS revealed that Nrf1 directly and indirectly regulates the genes related to amino acid and lipid catabolism, suggesting that the dysregulation of these metabolic genes is associated with liver phenotypes of Nrf1 knockout mice.
Molecular Mechanisms of Adaptive Responses to Food and Oxygen

YAMAMOTO Masayuki, KATSUOKA Fumiki, MINEGISHI Naoko, MOTOHASHI Hozumi, KUROKAWA Hirofumi, SUZUKI Norio, MORIGUCHI Takashi, SUZUKI Takafumi, TAGUCHI Keiko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Creative Scientific Research

Institution: Tohoku University

2007 - 2011

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Environmental stress response system allows organisms to keep cellular homeostasis. In this study, weexamined Keap1-Nrf2-mediated oxidative and xenobiotic defense system, and identified novel molecular mechanisms for stress-sensing system and their association with diseases. We alsoidentified diverse and elaborate gene regulatory mechanisms in response to hypoxic stressthrough the comprehensive analysis of erythropoietin gene regulatory regions.
転写因子Nrf1の神経細胞恒常性維持機構の解明

山本雅之, 勝岡史城

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 挑戦的萌芽研究

Institution: 東北大学

2010 - 2010

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アルツハイマー病、パーキンソン氏病などに代表される神経変性疾患は、高齢化社会において、生活の質を脅かす疾患の一つである。そかし、その病態の発症・進行の機構は不明な点が多い。bZIP型転写因子のNrf1の欠失マウスは、異常タンパク質の蓄積を伴ったヒトの進行性神経変性疾患に極めて類似した症状を示す。本計画では、Nrf1欠失マウスの解析を通して、その破綻・異常タンパク質の蓄積に至る分子機構を理解することで、ヒトの神経変性疾患に対する新たな知見を得ることを目的とする。 Nrf1欠失マウス由来の神経初代培養細胞を用いたマイクロアレイ解析を実施した。その結果、Nrf1の欠失で発現に影響を受ける遺伝子は、これまでに報告されてきたNrf2が制御する生体防御関連の標的遺伝子とは異なる事が示された。また、Nrf1欠失マウス脳組織においての遺伝子発現解析を実施し、同様の結果を得ている。したがって、Nrf1は、Nrf2とは異なる標的遺伝子の発現制御を介して、神経細胞の恒常性の維持に寄与していると考えられた。Nrf1が直接制御する標的遺伝子の同定を試みるために、Nrf1のクロマチン免疫沈降解析(ChIP)を計画した。ChIP解析に用いる抗体の検討を行ったが特異性の高い抗体は得られなかったので、申請計画に記したように、Nrf1のパートナー因子である小Maf群因子に対する抗体を用いて、ChIPシークエンス解析を実施した。その結果、小Mafの結合部位は、Ataxin-1などの神経変性と関連した遺伝子の制御領域に結合していることが明らかなり、病態発症との関連が示唆された。上記の結果の一部は、学会発表として報告し、また、誌上発表の予定である。
Generation of conditional knockout of small Maf genes in mice

KATSUOKA Fumiki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Young Scientists (B)

Institution: Tohoku University

2009 - 2010

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CNC-small Maf heterodimers are important for the regulation of various cytoprotective genes. This study revealed that small Maf proteins are indispensable for embryogenesis after E9.5, especially for liver development. This study also showed that the neurodegeneration observed in small Maf mutant mice is cell-autonomous effect. Conditional knockout system of small Maf proteins was established and will enable us to examine the function of small Maf proteins in adult tissues.
Functional domain analysis of Nrf2 and small Maf proteins

KATSUOKA Fumiki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Young Scientists (Start-up)

2007 - 2008

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