研究者詳細

顔写真

オオツキ　アキヒト
大槻　晃史
Akihito Otsuki
所属
東北メディカル・メガバンク機構　ゲノム解析部門
職名
講師
学位

  • 博士（医学） （東北大学）

経歴 5

  • 2023年4月 ～ 継続中
    東北大学　東北メディカル・メガバンク機構　講師

  • 2017年4月 ～ 2023年3月
    東北大学　東北メディカル・メガバンク機構　助教

  • 2016年4月 ～ 2017年3月
    東北医科薬科大学　医学部　助教

  • 2015年4月 ～ 2016年3月
    日本学術振興会　特別研究員

  • 2011年4月 ～ 2012年3月
    東北大学病院　医員

学歴 2

  • 東北大学　大学院医学系研究科

    2012年4月 ～ 2016年3月

  • 東北大学　歯学部

    2005年4月 ～ 2011年3月

所属学協会 2

  • 日本分子生物学会

    2018年7月 ～ 継続中

  • 日本生化学会

    2015年 ～ 継続中

研究キーワード 3

  • 酸化ストレス

  • ゲノム解析

  • 分子生物学

研究分野 1

  • ライフサイエンス / 医化学 /

受賞 4

  1. 令和5年度日本生化学会東北支部 奨励賞

    2023年6月

  2. 令和4年度宮城県医師会医学奨励賞

    2023年1月

  3. 令和4年度東北大学医学部奨学賞 銀賞

    2023年1月

  4. 平成28年度日本生化学会東北支部 優秀論文賞

    2016年5月

論文 43

  1. ibSLS as a biobank for democratizing access to multi-omics data and biospecimens from spaceflight research. 国際誌 査読有り

    Akihito Otsuki, Yuichi Aoki, Risa Okada, Liam Baird, Daisuke Kamimura, Dai Shiba, Eiji Hishinuma, Seizo Koshiba, Fumiki Katsuoka, Kengo Kinoshita, Takafumi Suzuki, Akira Uruno, Masayuki Yamamoto

    Nature communications　17　(1)　2026年8月20日

    DOI： 10.1038/s41467-026-76349-y 　

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    During spaceflight, astronauts are exposed to extreme conditions such as microgravity, cosmic radiation, and confinement, which can cause a wide range of health problems. To elucidate the molecular mechanisms underlying these issues and to develop intervention strategies for maintaining physiological homeostasis during space missions, space life science research using mouse models is actively conducted on the International Space Station (ISS). However, because of the high cost and technical complexity of spaceflight experiments, it is essential to maximize the scientific value of each mission by ensuring broad accessibility to both data and biospecimens. To this end, we present the integrated biobank for Space Life Science (ibSLS; https://ibsls.megabank.tohoku.ac.jp ), a data-visualization and sample-sharing platform that provides access to transcriptomic and metabolomic datasets generated from Mouse Habitat Unit (MHU) missions conducted by the Japan Aerospace Exploration Agency (JAXA). The platform features a user-friendly interface, tools for cross-mission analysis, and links to human multi-omics databases to support cross-species interpretation. In addition, ibSLS facilitates biospecimen requests to support downstream research. By promoting open access to spaceflight-derived data and biological resources, ibSLS encourages the participation of researchers from diverse fields in space life science.

  2. Advancements in Whole-Genome Sequencing Protocols: A Decade of In-House Operations and Quality Controls at the Tohoku Medical Megabank. 査読有り

    Fumiki Katsuoka, Junko Kawashima, Shu Tadaka, Akihito Otsuki, Yasunobu Okamura, Takafumi Suzuki, Takanori Hidaka, Kazuki Kumada, Fuji Nagami, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto

    JMA journal　8　(4)　1039-1052　2025年10月15日

    DOI： 10.31662/jmaj.2025-0159 　

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    Population-scale human whole-genome sequencing (WGS) projects are ongoing worldwide. At a time when such large-scale genome projects were uncommon, the Tohoku Medical Megabank Project initiated genome analysis of the general population in Japan, aiming to build a foundation for personalized medicine and prevention. Recently, we have completed the WGS of 100,000 participants, and research utilizing this genomic foundation is in progress. Early in the project, we realized that standard protocols were not always suitable for large-scale sequencing, necessitating the development of optimized operations and quality control methods. To accommodate various sequencing platforms and adapt protocols to the scale of analysis, we have continuously refined our methods. As multiplex sequencing analysis became standard, we aimed to ensure uniform data quantity across samples. With the advent of large-scale analyses, streamlining operations has also been a critical focus. In this paper, we share the details of our WGS operations and quality control methods developed over a decade, highlighting the unique methods and know-how we have established.

  3. JG2: an updated version of the Japanese population-specific reference genome 査読有り

    Sirawit Sriwichaiin, Satoshi Makino, Takamitsu Funayama, Akihito Otsuki, Junko Kawashima, Yasunobu Okamura, Shu Tadaka, Fumiki Katsuoka, Kazuki Kumada, Shuichi Tsutsumi, Kengo Kinoshita, Masayuki Yamamoto, Gen Tamiya, Jun Takayama

    Human Genome Variation　12　(1)　2025年10月1日

    出版者・発行元： Springer Science and Business Media LLC

    DOI： 10.1038/s41439-025-00326-y 　

    eISSN：2054-345X

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    Abstract Here we present the construction of JG2, an updated population-specific reference genome for the Japanese population. Utilizing data from three individuals previously used in the construction of JG1, several methodologies were employed to enhance genomic coverage and assembly quality. Hi-C sequencing technology facilitated phase-aware assembly, generating two haploid assemblies per individual and enabling improved representation of genetic variation. A meta-assembly strategy and a majority decision approach further refined assembly quality by combining the best sequences from multiple assemblies and minimizing the inclusion of rare variants. The resulting JG2 genome comprises chromosome-level sequences, mitochondrial chromosomes and unplaced scaffolds, offering more comprehensive coverage of the Japanese genome. Comparative analyses with other reference genomes demonstrated the accuracy and representativeness of JG2, highlighting its utility for genetic research involving the Japanese population. Overall, by adopting the phased assembly technique, JG2 represents a substantial advancement over the collapsed assembly-based JG1, with improvements including a greater number of identified variants (3,115,695 variants, of which 298,644 had an allele frequency (AF) of 1.0 in the 3.5KJPNv2 AF panel) and a higher N50 value (152,668,378 bp). These enhancements provide researchers with a more precise and comprehensive resource for understanding the genetic landscape of the Japanese population. The sequences and annotations are available on the jMorp website (https://jmorp.megabank.tohoku.ac.jp/).

  4. ibSLS: A Biobank for Democratizing Access to Multi-Omics Data and Biospecimens from Spaceflight Research

    Akihito Otsuki, Yuichi Aoki, Risa Okada, Daisuke Kamimura, Dai Shiba, Eiji Hishinuma, Seizo Koshiba, Fumiki Katsuoka, Kengo Kinoshita, Takafumi Suzuki, Akira Uruno, Masayuki Yamamoto

    2025年9月12日

    出版者・発行元： openRxiv

    DOI： 10.1101/2025.09.08.675003 　

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    Abstract During spaceflight, astronauts are exposed to extreme conditions such as microgravity, cosmic radiation, and confinement, which can cause a wide range of health problems. To elucidate the molecular mechanisms underlying these issues and to develop intervention strategies for maintaining physiological homeostasis during space missions, space life science research using mouse models is actively conducted on the International Space Station (ISS). However, because of the high cost and technical complexity of spaceflight experiments, it is critical to maximize the scientific value of each mission by ensuring broad accessibility to both data and biospecimens. To this end, we developed the integrated biobank for Space Life Sciences (ibSLS; https://ibsls.megabank.tohoku.ac.jp ), a data-visualization and sample-sharing platform that provides access to transcriptomic and metabolomic datasets generated from JAXA’s Mouse Habitat Unit (MHU) missions. The platform features a user-friendly interface, tools for cross-mission analysis, and integration with human multi-omics databases, enabling cross-species comparisons. In addition, ibSLS facilitates biospecimen requests to support downstream research. By promoting open access to spaceflight-derived data and biological resources, ibSLS encourages the participation of researchers from diverse fields in space life science. We believe that ibSLS will make a valuable contribution to both biomedical research on spaceflight-related health issues and the study of diseases on Earth.

  5. Construction of a trio-based structural variation panel utilizing activated T lymphocytes and long-read sequencing technology 国際誌 査読有り

    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年9月20日

    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.

  6. Japonica Array NEO with increased genome-wide coverage and abundant disease risk SNPs 国際誌 査読有り

    Mika Sakurai-Yageta, Kazuki Kumada, Chinatsu Gocho, Satoshi Makino, Akira Uruno, Shu Tadaka, Ikuko N Motoike, Masae Kimura, Shin Ito, Akihito Otsuki, Akira Narita, Hisaaki Kudo, Yuichi Aoki, Inaho Danjoh, Jun Yasuda, Hiroshi Kawame, Naoko Minegishi, Seizo Koshiba, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

    The Journal of Biochemistry　170　(3)　399-410　2021年5月13日

    出版者・発行元： Oxford University Press (OUP)

    DOI： 10.1093/jb/mvab060 　

    ISSN：0021-924X

    eISSN：1756-2651

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    <title>Abstract</title> Ethnic-specific SNP arrays are becoming more important to increase the power of genome-wide association studies in diverse population. In the Tohoku Medical Megabank Project, we have been developing a series of Japonica Arrays (JPA) for genotyping participants based on reference panels constructed from whole-genome sequence data of the Japanese population. Here, we designed a novel version of the SNP array for the Japanese population, called Japonica Array NEO (JPA NEO), comprising a total of 666,883 markers. Among them, 654,246 tag SNPs of autosomes and X chromosome were selected from an expanded reference panel of 3,552 Japanese, 3.5KJPNv2, using pairwise r2 of linkage disequilibrium measures. Additionally, 28,298 markers were included for the evaluation of previously identified disease risk markers from the literature and databases, and those present in the Japanese population were extracted using the reference panel. Through genotyping 286 Japanese samples, we found that the imputation quality r2 and INFO score in the minor allele frequency bin &amp;gt;2.5–5% were &amp;gt;0.9 and &amp;gt;0.8, respectively, and &amp;gt;12 million markers were imputed with an INFO score &amp;gt;0.8. From these results, JPA NEO is a promising tool for genotyping the Japanese population with genome-wide coverage, contributing to the development of genetic risk scores.

  7. Identification of Dominant Transcripts in Oxidative Stress Response by a Full-Length Transcriptome Analysis. 国際誌 査読有り

    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年1月25日

    出版者・発行元： American Society for Microbiology

    DOI： 10.1128/MCB.00472-20 　

    ISSN：0270-7306 1098-5549

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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.

  8. Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference. 国際誌 査読有り

    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年1月11日

    出版者・発行元： Cold Spring Harbor Laboratory

    DOI： 10.1038/s41467-020-20146-8 　

    ISSN：2041-1723

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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.

  9. Nrf2 contributes to the weight gain of mice during space travel. 国際誌 査読有り

    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年9月8日

    出版者・発行元： Springer Science and Business Media {LLC}

    DOI： 10.1038/s42003-020-01227-2 　

    ISSN：2399-3642

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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.

  10. Cis-element architecture of Nrf2-sMaf heterodimer binding sites and its relation to diseases. 国際誌 査読有り

    Akihito Otsuki, Masayuki Yamamoto

    Archives of pharmacal research　43　(3)　275-285　2020年3月

    DOI： 10.1007/s12272-019-01193-2 　

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    Cellular detoxication is essential for health because it provides protection against various chemicals and xenobiotics. The KEAP1-NRF2 system is important for cellular defense against oxidative and electrophilic stresses as NRF2 activates the transcription of an array of cytoprotective genes, including drug-metabolizing and antioxidant enzymes, in a stress-dependent manner. The CNC family of transcription factors, including NRF2, form heterodimers with small Maf (sMaf) proteins and bind to consensus DNA sequences that have been referred to as antioxidant response element, electrophile response element, or NF-E2-binding element. These sequences are now collectively called CNC-sMaf binding element (CsMBE). In addition to forming a heterodimer with CNC proteins, sMaf proteins can form homodimers and recognize regulatory motifs called Maf recognition element (MARE). Although the CsMBE sequence substantially overlaps with that of MARE, the sequences differ. NRF2 selectively recognizes CsMBE, which is critical for cytoprotection. Recent advances in high-throughput sequencing and population-scale genome analysis provide new insights into the transcriptional regulation involved in the stress response. The integration of a genome-wide map of NRF2 occupancy with disease-susceptibility loci reveals the associations between polymorphisms in CsMBE and disease risk, information useful for the personalized medicine of the future.

  11. 3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. 国際誌 査読有り

    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　(1)　28-28　2019年

    出版者・発行元： Springer Science and Business Media {LLC}

    DOI： 10.1038/s41439-019-0059-5 　

    ISSN：2054-345X

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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.

  12. [CNC-small Maf heterodimer: Unique cis-element recognition and biological functions]. 査読有り

    Akihito Otsuki, Masayuki Yamamoto

    Seikagaku. The Journal of Japanese Biochemical Society　89　(2)　278-81　2017年4月

    出版者・発行元： Japanese Biochemical Society

    DOI： 10.14952/SEIKAGAKU.2017.890278 　

    ISSN：0037-1017

  13. Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection. 国際誌 査読有り

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

    Free radical biology & medicine　91　45-57　2016年2月

    DOI： 10.1016/j.freeradbiomed.2015.12.005 　

    ISSN：0891-5849

    eISSN：1873-4596

  14. BCL11B enhancer hijacking by t(14;16)(q32;q24) translocation defines a novel high-risk subtype of T-ALL. 国際誌 査読有り

    Kaito Mimura, Akira Kaino, Yotaro Ochi, Yu-Hsuan Chang, Masafumi Seki, June Takeda, Saori Katayama, Hidetaka Niizuma, Yoji Sasahara, Yoko Mizoguchi, Maiko Shimomura, Ryosuke Koyamada, Rintaro Ono, Daisuke Hasegawa, Kazuki Mitani, Hirohito Kubota, Satoshi Yoshihara, Nobuhiro Hiramoto, Akihito Otsuki, Yasunobu Okamura, Fumiki Katsuoka, Kengo Kinoshita, Masataka Hasegawa, Marina Togo-Ohno, Hirona Maeda, Nobuyuki Kakiuchi, Mai Takeuchi, Aiko Sato-Otsubo, Shota Kato, Kentaro Watanabe, Kotoe Katayama, Seiya Imoto, Yuichi Shiraishi, Katsuyoshi Koh, Souichi Suenobu, Eiso Hiyama, Susumu Goyama, Atsuo Kikuchi, Seishi Ogawa, Motohiro Kato, Yasuhito Nannya, Junko Takita, Kenichi Yoshida

    Blood　148　(3)　335-347　2026年7月16日

    DOI： 10.1182/blood.2025031466 　

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    The molecular classification of T-cell acute lymphoblastic leukemia (T-ALL) remains incomplete, limiting risk stratification and the development of targeted therapies. Enhancer hijacking is a critical oncogenic mechanism that deregulates proto-oncogenes by repositioning cis-regulatory regions via structural variants. Here, we performed an integrated analysis of pediatric and adult T-ALL and mixed phenotype acute leukemias (MPALs), using whole-genome and whole-transcriptome sequencing. This analysis identified a group of 14 patients with predominantly T-lineage neoplasms driven by a t(14;16)(q32;q24) translocation, harboring universal GATA3 mutations and CDKN2A/B deletions. Mechanistically, this translocation repositions the ThymoD locus downstream of BCL11B, causing monoallelic, ectopic overexpression of FENDRR and mesenchymal transcription factor genes FOXF1 and FOXC2, activating epithelial-mesenchymal transition (EMT) transcription signatures. Immunophenotypic and single-cell RNA-seq analyses revealed marked lineage ambiguity with myeloid and B-cell differentiation potentials specific to this subtype. Furthermore, functional analyses in CD34-positive cord blood cells demonstrated that FOXF1 overexpression promotes myeloid differentiation while suppressing T-cell differentiation, serving as a key factor for lineage specification. Clinically, this subtype was detected in 0.15-4.0% of T-ALL/MPAL cases depending on the cohort, showing a median age of 15 years and enrichment in adolescents and young adults (AYA). Importantly, patients with t(14;16)(q32;q24) have an extremely poor prognosis, showing a trend toward worse outcomes than high-risk groups such as KMT2A-rearranged early T-cell progenitor (ETP)-like, SPI1-rearranged, and LMO2 γδ-like T-ALLs. The unique molecular landscape and poor prognosis of patients with the t(14;16)(q32;q24) translocation underscore the need for the development of novel subtype-specific therapeutic approaches.

  15. 0.33G Mitigates Muscle Atrophy While 0.67G Preserves Muscle Function and Myofiber Type Composition in Mice during Spaceflight 査読有り

    Michito Hamada, Martha Vitaterna, Akane Yumoto, Seizo Koshiba, Risa Okada, Takashi Kudo, Daisuke Kamimura, Masayuki Yamamoto, Shunya Sadaki, Ryosuke Tsuji, Takuto Hayashi, Yuri Inoue, Yuka Murakami, Hiroe Kobayashi, Maki Okada, Charles Fuller, Ryo Fujita, Ryo Kurosawa, Marie Mortreux, Mary Bouxsein, Masafumi Muratani, Seward Rutkove, Tatsuya Matsumoto, Takafumi Suzuki, Jennifer Coulombe, Jason Ciola, Akihito Otsuki, Dai Shiba, Dong-Min Sung, Satoru Takahashi

    Science Advances　2026年3月13日

    DOI： 10.1126/sciadv.aed2258 　

  16. Cisplatin-induced genetic alterations in KEAP1 promote therapeutic resistance in head and neck squamous cell carcinoma. 国際誌 査読有り

    Yuki Nakayama, Keiko Taguchi, Shun Wakamori, Akira Uruno, Akihito Otsuki, Akira Ohkoshi, Hidekazu Shirota, Tomoyuki Iwasaki, Yukio Katori, Masayuki Yamamoto

    Redox biology　86　103819-103819　2025年10月

    DOI： 10.1016/j.redox.2025.103819 　

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    Cisplatin (CDDP) resistance remains a major challenge in the treatment of recurrent head and neck squamous cell carcinoma (HNSCC). The KEAP1-NRF2 system, a central regulator of cellular redox homeostasis, is frequently altered in cancer, but its contribution to acquired CDDP resistance in HNSCC remains to be clarified. To address this, we investigated NRF2 activation in CDDP resistance using seven parental (P) HNSCC cell lines and their CDDP-resistant (CR) derivatives. Among these P-CR pairs, three CR lines exhibited elevated NRF2 expression; two harbored KEAP1 mutations, and one had an NFE2L2 mutation that were present in both P and CR lines. These NRF2-high CR lines showed upregulation of NRF2 target genes and enrichment of xenobiotic metabolism and reactive oxygen species pathways. Mitomycin C (MMC), a cytotoxic agent for its synthetic lethality in NRF2-activated cancer cells, demonstrated strong cytotoxicity specifically in these NRF2-high CR lines. Immunohistochemical analysis on clinical samples found that high NRF2 expression was significantly associated with poor prognosis and was frequently observed in recurrent tumors following chemoradiotherapy with CDDP. These results suggest that CDDP therapy, while initially effective, may paradoxically promote tumor progression and therapeutic resistance by aberrantly activating the KEAP1-NRF2 axis. This redox-driven adaptation highlights a critical characteristic in NRF2-hyperactivated HNSCC that is exploitable by MMC treatment.

  17. Specific cancer types and prognosis in patients with variations in the <scp>KEAP1</scp>‐<scp>NRF2</scp> system: A retrospective cohort study 査読有り

    Tomoyuki Iwasaki, Hidekazu Shirota, Keiju Sasaki, Kota Ouchi, Yuki Nakayama, Hiroyuki Oshikiri, Akihito Otsuki, Takafumi Suzuki, Masayuki Yamamoto, Chikashi Ishioka

    Cancer Science　2024年9月26日

    DOI： 10.1111/cas.16355 　

    ISSN：1347-9032 1349-7006

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    <jats:title>Abstract</jats:title><jats:p>The KEAP1–NRF2 system induces the expression of antioxidant genes in response to various types of oxidative stress. Some cancer cells activate this system, which increases their malignancy through genetic mutations. We performed a retrospective cohort study using the C‐CAT database, which contains the gene‐panel sequence data from 60,056 cases of diagnosed solid tumors. We analyzed somatic mutations in <jats:italic>NRF2</jats:italic> and <jats:italic>KEAP1</jats:italic> genes and their associations with clinical outcomes. Variants in the <jats:italic>NRF2</jats:italic> gene were clustered in exon 2, which encodes the DLG and ETGE motifs essential for KEAP1 interaction. The <jats:italic>NRF2</jats:italic> variants were frequently observed in esophageal and lung squamous cell carcinoma with frequencies of 35.9% and 19.6%, respectively. Among these mutations, the <jats:italic>NRF2</jats:italic> variants in the ETGE motif were indicators of a worse prognosis. <jats:italic>KEAP1</jats:italic> variants were found in 2.5% of all cases. The variants were frequent in lung cancer and showed a worse prognosis in lung and other types of adenocarcinomas. We then conducted gene expression analysis using TCGA data. While cancers with DLG and ETGE variants were similar in terms of gene expression profiles, there were significant differences between cancers with <jats:italic>KEAP1</jats:italic> and <jats:italic>NRF2</jats:italic> variants. Our results indicate that genetic alteration of the KEAP1–NRF2 pathway is a major factor in patient prognosis for each cancer type and its genetic variant. Variants in <jats:italic>NRF2</jats:italic> and <jats:italic>KEAP1</jats:italic> genes can characterize the biological basis of each cancer type and are involved in carcinogenesis, resistance to therapy, and other biological differences.</jats:p>

  18. Progress report of the Tohoku Medical Megabank Community-Based Cohort Study: Study profile of the repeated center-based survey during second period in Miyagi Prefecture. 査読有り

    Atsushi Hozawa, Kumi Nakaya, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Ippei Chiba, Ikumi Kanno, Junichi Sugawara, Eiichi Kodama, Yohei Hamanaka, Tomoko Kobayashi, Akira Uruno, Naho Tsuchiya, Takumi Hirata, Akira Narita, Akito Tsuboi, Toru Tamahara, Akihito Otsuki, Maki Goto, Makiko Taira, Ritsuko Shimizu, Kichiya Suzuki, Taku Obara, Masahiro Kikuya, Hirohito Metoki, Mami Ishikuro, Inaho Danjoh, Soichi Ogishima, Satoshi Nagaie, Naoko Minegishi, Masahiro Hiratsuka, Kazuki Kumada, Ichiko Nishijima, Takahiro Nobukuni, Yumi Yamaguchi-Kabata, Fuji Nagami, Shigeo Kure, Nobuo Fuse, Kengo Kinoshita, Yoko Izumi, Shinichi Kuriyama, Masayuki Yamamoto

    Journal of epidemiology　2024年2月24日

    DOI： 10.2188/jea.JE20230241 　

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    BACKGROUND: The purpose of this study was to report the basic profile of the Miyagi Prefecture part of a repeated center-based survey during the second period (2nd period survey) of the Tohoku Medical Megabank Community-Based Cohort Study (TMM CommCohort Study), as well as the participants' characteristics based on their participation type in the baseline survey. METHODS: The 2nd period survey, conducted from June 2017 to March 2021, included participants of the TMM CommCohort Study (May 2013 to March 2016). In addition to the questionnaire, blood, urine, and physiological function tests were performed during the 2nd period survey. There were three main ways of participation in the baseline survey: Type 1, Type 1 additional, or Type 2 survey. The 2nd period survey was conducted in the same manner as the Type 2 survey, which was based on the community support center (CSC). RESULTS: In Miyagi Prefecture, 29,383 (57.7%) of 50,967 participants participated in the 2nd period survey. The participation rate among individuals who had visited the CSC was approximately 80%. Although some factors differed depending on the participation type in the baseline survey, the 2nd period survey respondents in the Type 1 and Type 2 survey groups at baseline had similar traits. CONCLUSIONS: The 2nd period survey of the TMM CommCohort Study provided detailed follow-up information. Following up on the health conditions of the participants will clarify the long-term effects of disasters and contribute to personalized prevention.

  19. Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals. 国際誌 査読有り

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

    Journal of biochemistry　2024年1月24日

    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.

  20. Effects of NRF2 polymorphisms on safety and efficacy of bardoxolone methyl: subanalysis of TSUBAKI study 査読有り

    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年11月14日

    DOI： 10.1007/s10157-023-02427-w 　

  21. jMorp: Japanese Multi-Omics Reference Panel update report 2023. 国際誌 査読有り

    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年11月1日

    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.

  22. Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice 査読有り

    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年8月

    DOI： 10.1038/s42003-022-03316-w 　

  23. Design and Progress of Child Health Assessments at Community Support Centers in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank Project. 査読有り

    Tomoko Kobayashi, Mika Kobayashi, Naoko Minegishi, Masahiro Kikuya, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Tomomi Onuma, Keiko Murakami, Fumihiko Ueno, Aoi Noda, Akira Uruno, Junichi Sugawara, Kichiya Suzuki, Eiichi N Kodama, Yohei Hamanaka, Naho Tsuchiya, Mana Kogure, Naoki Nakaya, Makiko Taira, Mika Sakurai-Yageta, Toru Tamahara, Junko Kawashima, Maki Goto, Akihito Otsuki, Ritsuko Shimizu, Soichi Ogishima, Hiroaki Hashizume, Fuji Nagami, Tomohiro Nakamura, Atsushi Hozawa, Tadao Kobayashi, Nobuo Fuse, Shinichi Kuriyama, Shigeo Kure, Masayuki Yamamoto

    The Tohoku journal of experimental medicine　259　(2)　93-105　2022年12月1日

    DOI： 10.1620/tjem.2022.J103 　

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    The Tohoku Medical Megabank Project (TMM) has been conducting a birth and three-generation cohort study (the BirThree Cohort Study). We recruited 73,529 pregnant women and their family members for this cohort study, which included 23,143 newborns and 9,459 of their siblings. We designed and are in the process of conducting three-step health assessments for each newborn at approximately ages of 5, 10 and 16. These health assessments are administered at seven community support centers. Trained genome medical research coordinators conduct physical examinations of and collect biological specimens from each participant. The Sendai Children's Health Square has been established as the headquarters for these child health assessments and is utilized to accumulate knowledge that can facilitate the proper practice of child health assessments. We designed all the relevant health assessments facilities to allow parents and their children to participate in the health assessments concomitantly. Our centers serve as places where child participants and their parents can feel at ease as a result of the implementation of safety measures and child hospitality measures. The TMM BirThree Cohort Study is in the process of conducting strategically detailed health assessments and genome analysis, which can facilitate studies concerning the gene-environment interactions relevant to noncommunicable diseases. Through these operations, our study allows for a significant depth of data to be collected in terms of the number of biospecimens under study and the comprehensiveness of both basic and clinical data alongside relevant family information.

  24. The Il6 -39 kb enhancer containing clustered GATA2- and PU.1-binding sites is essential for Il6 expression in murine mast cells. 国際誌 査読有り

    Shin'ya Ohmori, Jun Takai, Satoshi Uemura, Akihito Otsuki, Tetsuya Mori, Kinuko Ohneda, Takashi Moriguchi

    iScience　25　(9)　104942-104942　2022年9月16日

    出版者・発行元： Elsevier {BV}

    DOI： 10.1016/j.isci.2022.104942 　

    ISSN：2589-0042

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    Mast cells serve as a first-line defense of innate immunity. Interleukin-6 (IL-6) induced by bacterial lipopolysaccharide (LPS) in mast cells plays a crucial role in antibacterial protection. The zinc finger transcription factor GATA2 cooperatively functions with the ETS family transcription factor PU.1 in multiple mast cell activities. However, the regulatory landscape directed by GATA2 and PU.1 under inflammation remains elusive. We herein showed that a large proportion of GATA2-binding peaks were closely located with PU.1-binding peaks in distal cis-regulatory regions of inflammatory cytokine genes in mast cells. Notably, GATA2 and PU.1 played crucial roles in promoting LPS-mediated inflammatory cytokine production. Genetic ablation of GATA2-PU.1-clustered binding sites at the Il6 -39 kb region revealed its central role in LPS-induced Il6 expression in mast cells. We demonstrate a novel collaborative activity of GATA2 and PU.1 in cytokine induction upon inflammatory stimuli via the GATA2-PU.1 overlapping sites in the distal cis-regulatory regions.

  25. The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 Degradation In Vivo. 国際誌 査読有り

    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年7月21日

    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.

  26. Target Gene Diversity of the Nrf1-MafG Transcription Factor Revealed by a Tethered Heterodimer. 国際誌 査読有り

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

    Molecular and cellular biology　42　(3)　mcb0052021　2022年2月7日

    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 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.

  27. Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel. 国際誌 査読有り

    Norio Suzuki, Yuma Iwamura, Taku Nakai, Koichiro Kato, Akihito Otsuki, Akira Uruno, Daisuke Saigusa, Keiko Taguchi, Mikiko Suzuki, Ritsuko Shimizu, Akane Yumoto, Risa Okada, Masaki Shirakawa, Dai Shiba, Satoru Takahashi, Takafumi Suzuki, Masayuki Yamamoto

    Kidney international　101　(1)　92-105　2022年1月

    出版者・発行元： Elsevier {BV}

    DOI： 10.1016/j.kint.2021.09.031 　

    ISSN：0085-2538

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    Space travel burdens health by imposing considerable environmental stress associated with radioactivity and microgravity. In particular, gravity change predominantly impacts blood pressure and bone homeostasis, both of which are controlled mainly by the kidneys. Nuclear factor erythroid-2-related transcription factor 2 (Nrf2) plays essential roles in protecting the kidneys from various environmental stresses and injuries. To elucidate the effects of space travel on mammals in preparation for the upcoming space era, our study investigated the contribution of Nrf2 to kidney function in mice two days after their return from a 31-day stay in the International Space Station using Nrf2 knockout mice. Meaningfully, expression levels of genes regulating bone mineralization, blood pressure and lipid metabolism were found to be significantly altered in the kidneys after space travel in an Nrf2-independent manner. In particular, uridine diphosphate-glucuronosyltransferase 1A (Ugt1a) isoform genes were found to be expressed in an Nrf2-dependent manner and induced exclusively in the kidneys after return to Earth. Since spaceflight elevated the concentrations of fatty acids in the mouse plasma, we suggest that Ugt1a isoform expression in the kidneys was induced to promote glucuronidation of excessively accumulated lipids and excrete them into urine after the return from space. Thus, the kidneys were proven to play central roles in adaptation to gravity changes caused by going to and returning from space by controlling blood pressure and bone mineralization. Additionally, kidney Ugt1a isoform induction after space travel implies a significant role of the kidneys for space travelers in the excretion of excessive lipids.

  28. Nrf2 plays a critical role in the metabolic response during and after spaceflight. 国際誌 査読有り

    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年12月9日

    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.

  29. jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population. 国際誌 査読有り

    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-D544　2021年1月8日

    出版者・発行元： Oxford University Press ({OUP})

    DOI： 10.1093/nar/gkaa1034 　

    ISSN：0305-1048 1362-4962

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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.

  30. dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project 査読有り

    Ogishima, S., Nagaie, S., Mizuno, S., Ishiwata, R., Iida, K., Shimokawa, K., Takai-Igarashi, T., Nakamura, N., Nagase, S., Nakamura, T., Tsuchiya, N., Nakaya, N., Murakami, K., Ueno, F., Onuma, T., Ishikuro, M., Obara, T., Mugikura, S., Tomita, H., Uruno, A., Kobayashi, T., Tsuboi, A., Tadaka, S., Katsuoka, F., Narita, A., Sakurai, M., Makino, S., Tamiya, G., Aoki, Y., Shimizu, R., Motoike, I.N., Koshiba, S., Minegishi, N., Kumada, K., Nobukuni, T., Suzuki, K., Danjoh, I., Nagami, F., Tanno, K., Ohmomo, H., Asahi, K., Shimizu, A., Hozawa, A., Kuriyama, S., Yamamoto, M., Abe, M., Aizawa, Y., Aoki, Y., Chida, K., Danjoh, I., Egawa, S., Eto, A., Funayama, T., Fuse, N., Hamanaka, Y., Harada, Y., Hashizume, H., Higuchi, S., Hirano, S., Hirata, T., Hiratsuka, M., Hozawa, A., Igarashi, K., Inoue, J., Ishida, N., Ishii, N., Ishii, T., Ishikuro, M., Ito, K., Ito, S., Kageyama, M., Katsuoka, F., Kawame, H., Kawashima, J., Kikuya, M., Kinoshita, K., Kitatani, K., Kiyama, T., Kiyomoto, H., Kobayashi, T., Kodama, E., Kogure, M., Kojima, K., Koreeda, S., Koshiba, S., Koyama, S., Kudo, H., Kumada, K., Kure, S., Kuriki, M., Kuriyama, S., Kuroki, Y., Maikusa, N., Makino, S., Matsubara, H., Matsui, H., Metoki, H., Mimori, T., Minegishi, N., Misawa, K., Miyashita, M., Mizuno, S., Motohashi, H., Motoike, I.N., Nagaie, S., Nagai, M., Nagami, F., Nagasaki, M., Nagase, S., Nakamura, N., Nakamura, T., Nakaya, N., Nakayama, K., Narita, A., Nishijima, I., Nobukuni, T., Nochioka, K., Obara, T., Ogishima, S., Ohuchi, N., Olivier, G., Osumi, N., Otsu, H., Otsuki, A., Saigusa, D., Saito, S., Saito, T., Sakaida, M., Sakurai-Yageta, M., Sato, Y., Sato, Y., Sekiguchi, A., Shen, C.-Y., Shibata, T.F., Shimizu, R., Shimokawa, K., Shirota, M., Sugawara, J., Suzuki, K., Suzuki, Y., Tadaka, S., Taira, M., Takai-Igarashi, T., Takano, Y., Taki, Y., Tanabe, O., Tanaka, H., Tanaka, Y., Teraguchi, S., Terakawa, T., Tominaga, T., Tomita, H., Tsuboi, A., Tsuchiya, N., Tsuji, I., Ueki, M., Uruno, A., Yaegashi, N., Yamagishi, J., Yamaguchi-Kabata, Y., Yamanaka, C., Yamashita, R., Yasuda, J., Yokozawa, J., Waki, K., Sasaki, M., Akai, J., Endo, R., Fukushima, A., Furukawa, R., Hachiya, T., Hashizume, K., Hitomi, J., Ishigaki, Y., Komaki, S., Kotozaki, Y., Mikami, T., Nakamura, M., Nishiya, N., Nishizuka, S., Nomura, Y., Ogasawara, K., Ohmomo, H., Omama, S., Otomo, R., Otsuka, K., Oyama, K., Sakata, K., Sasaki, R., Satoh, M., Sato, N., Shimizu, A., Shiwa, Y., Sutoh, Y., Takanashi, N., Takebe, N., Tanaka, F., Tanaka, R., Tanno, K., Tokutomi, T., Yamamoto, K., Yamashita, F., Fuse, N., Tominaga, T., Kure, S., Kinoshita, K., Sasaki, M., Tanaka, H., Yamamoto, M.

    Human Genome Variation　8　(1)　2021年

    DOI： 10.1038/s41439-021-00175-5 　

    ISSN：2054-345X

  31. Landscape of electrophilic and inflammatory stress-mediated gene regulation in human lymphoblastoid cell lines. 国際誌 査読有り

    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年12月

    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.

  32. Author Correction: Nrf2 contributes to the weight gain of mice during space travel. 国際誌

    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)　566-566　2020年10月7日

    DOI： 10.1038/s42003-020-01292-7 　

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    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  33. Design and Progress of Oral Health Examinations in the Tohoku Medical Megabank Project. 査読有り

    Akito Tsuboi, Hiroyuki Matsui, Naru Shiraishi, Takahisa Murakami, Akihito Otsuki, Junko Kawashima, Tomomi Kiyama, Toru Tamahara, Maki Goto, Shihoko Koyama, Junichi Sugawara, Eiichi N Kodama, Hirohito Metoki, Atsushi Hozawa, Shinichi Kuriyama, Hiroaki Tomita, Masahiro Kikuya, Naoko Minegishi, Kichiya Suzuki, Seizo Koshiba, Gen Tamiya, Nobuo Fuse, Yuichi Aoki, Takako Takai-Igarashi, Soichi Ogishima, Tomohiro Nakamura, Mika Sakurai-Yageta, Fuji Nagami, Kengo Kinoshita, Shigeo Kure, Ritsuko Shimizu, Keiichi Sasaki, Masayuki Yamamoto

    The Tohoku journal of experimental medicine　251　(2)　97-115　2020年6月

    出版者・発行元： Tohoku University Medical Press

    DOI： 10.1620/tjem.251.97 　

    ISSN：0040-8727

    eISSN：1349-3329

    詳細を見る 詳細を閉じる

    In order to assess the long-term impact of the Great East Japan Earthquake on the oral health of disaster victims and to evaluate gene-environmental interactions in the development of major oral diseases and oral-systemic associations, the oral part of two large-scale genome cohort studies by the Tohoku Medical Megabank Organization (ToMMo), including the Community-based cohort (CommCohort) study and the Birth and Three-Generation cohort (BirThree) study, have been conducted. The study population comprised 32,185 subjects, including 16,886 participants in the CommCohort study and 15,299 participants in the BirThree cohort study, recruited from 2013 to 2017. The oral studies consist of a questionnaire regarding oral hygiene behavior, clinical examinations by dentists, and oral plaque and saliva sampling for microbiome analyses, which were carried out at seven community support centers in Miyagi prefecture. The median age of all participants was 55.0 years, and 66.1% of participants were women. Almost all participants reported that they brushed their teeth more than once a day. The median number of present teeth was 27.0, and the decayed, missing and filled tooth number was 16.0, with a significant difference according to age and sex. The median periodontal pocket and clinical attachment level was 2.48 mm and 4.00 mm, respectively. Periodontal parameters increased significantly according to age, except for the accumulation of dental calculus. The oral part of these extensive cross-sectional studies provides a unique and important platform for future studies on oral health and diseases that elicit through interactions with systemic diseases, lifestyles, life events and genetic backgrounds, and contributes to researches clarifying the long-term effects of disasters on oral health.

  34. Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells. 国際誌 査読有り

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

    Molecular and cellular biology　39　(20)　2019年10月15日

    出版者・発行元： American Society for Microbiology

    DOI： 10.1128/MCB.00273-19 　

    ISSN：0270-7306

    詳細を見る 詳細を閉じる

    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.

  35. Nrf2 activation in myeloid cells and endothelial cells differentially mitigates sickle cell disease pathology in mice. 国際誌 査読有り

    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年4月23日

    出版者・発行元： American Society of Hematology

    DOI： 10.1182/bloodadvances.2018017574 　

    ISSN：2473-9529

    詳細を見る 詳細を閉じる

    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.

  36. GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis. 国際誌 査読有り

    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年8月17日

    DOI： 10.1182/blood-2016-12-756767 　

    ISSN：0006-4971

    eISSN：1528-0020

  37. Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis. 国際誌 査読有り

    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年4月15日

    DOI： 10.1128/MCB.00592-16 　

    ISSN：0270-7306

    eISSN：1098-5549

  38. Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation. 国際誌 査読有り

    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年2月

    DOI： 10.1016/j.freeradbiomed.2016.12.041 　

    ISSN：0891-5849

    eISSN：1873-4596

  39. Gata3 Hypomorphic Mutant Mice Rescued with a Yeast Artificial Chromosome Transgene Suffer a Glomerular Mesangial Cell Defect. 国際誌 査読有り

    Takashi Moriguchi, Lei Yu, Akihito Otsuki, Keiko Ainoya, Kim-Chew Lim, Masayuki Yamamoto, James Douglas Engel

    Molecular and cellular biology　36　(17)　2272-81　2016年9月1日

    DOI： 10.1128/MCB.00173-16 　

    ISSN：0270-7306

    eISSN：1098-5549

  40. Keap1-Nrf2 System: Potential Role in Prevention of Sickle Cell Disease Organs Damages and Inflammation 査読有り

    Nadine Keleku-Lukwete, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, Takashi Moriguchi, Osamu Tanabe, James Doug Engel, Masue Imaizumi, Masayuki Yamamoto

    BLOOD　126　(23)　2015年12月

    ISSN：0006-4971

    eISSN：1528-0020

  41. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation. 国際誌 査読有り

    Nadine Keleku-Lukwete, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, Takashi Moriguchi, Osamu Tanabe, James Douglas Engel, Masue Imaizumi, Masayuki Yamamoto

    Proceedings of the National Academy of Sciences of the United States of America　112　(39)　12169-74　2015年9月29日

    DOI： 10.1073/pnas.1509158112 　

    ISSN：0027-8424

  42. A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. 国際誌 査読有り

    Hiromi Yamazaki, Mikiko Suzuki, Akihito Otsuki, Ritsuko Shimizu, Emery H Bresnick, James Douglas Engel, Masayuki Yamamoto

    Cancer cell　25　(4)　415-27　2014年4月14日

    DOI： 10.1016/j.ccr.2014.02.008 　

    ISSN：1535-6108

    eISSN：1878-3686

  43. Establishment of erythroleukemic GAK14 cells and characterization of GATA1 N-terminal domain 査読有り

    Harumi Y. Mukai, Mikiko Suzuki, Masumi Nagano, Shin'ya Ohmori, Akihito Otsuki, Kouhei Tsuchida, Takashi Moriguchi, Kinuko Ohneda, Ritsuko Shimizu, Osamu Ohneda, Masayuki Yamamoto

    Genes to Cells　18　(10)　886-898　2013年10月

    出版者・発行元： Wiley

    DOI： 10.1111/gtc.12084 　

    ISSN：1356-9597 1365-2443

︎全件表示 ︎最初の5件までを表示

MISC 1

  1. 日本人大規模ゲノム解析で同定されたCYP2D6遺伝子多型におけるバリアント酵素の機能変化

    西原翔大, 菱沼英史, 菱沼英史, CAROLINE Kijogi, 上田昭子, 鈴木佑眞, 大森悠生, 大槻晃史, 石田典子, 平塚真弘, 平塚真弘, 平塚真弘, 平塚真弘

    日本薬学会年会要旨集(Web)　145th　2025年

    ISSN： 0918-9823

講演・口頭発表等 13

  1. 長鎖リード解析によるバリアント参照パネル構築

    大槻晃史

    ToMMo-NCCE合同シンポジウム　2025年11月8日

  2. ゲノムを「読む」技術と「使う」未来 招待有り

    大槻晃史

    2025年度ToMMo GMRC交流研修会　2025年5月14日

  3. Genome Analysis for Dentistry and Medicine in Tohoku Medical Megabank 招待有り

    Akihito Otsuki

    The 71st Annual Meeting of Japanese Association for Dental Research

  4. ibSLS database: an integrated database for the exploration of environmental stress response during space flight,

    Akihito Otsuki, Yuichi Aoki, Akira Uruno, Risa Okada, Dai Shiba, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

    The Environmental Response VI

  5. 長鎖リードシークエンス技術による日本人ゲノム解析基盤構築 招待有り

    大槻晃史

    日本生化学会東北支部 第89回例会　2023年6月5日

  6. 長鎖リードシークエンス技術を用いた日本人ゲノム解析基盤の構築 招待有り

    大槻晃史

    第408回東北医学会例会　2023年1月12日

  7. 長鎖リードシークエンサーPromethIONを用いた日本人構造多型パネルJSV1の構築 招待有り

    大槻晃史

    日本人類遺伝学会第67回大会　2022年12月17日

  8. 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, 岡村容伸, 勝岡史城, 木下賢吾, 山本雅之

    第95回日本生化学会大会

  9. Maf認識配列を介した転写制御の破綻によって生じる致死的表現型の解析

    大槻晃史, 勝岡史城, 山本雅之

    第2回酸素生物学 & ダイイングコード合同若手会議

  10. 生体の酸化ストレス防御においてNrf2-sMafへテロ二量体によって認識される特殊なシス配列の重要性

    大槻晃史, 鈴木未来子, 勝岡史城, 守田匡伸, 清水律子, 山本雅之

    第89回生化学会大会

  11. 酸化ストレス応答におけるNrf2-sMafへテロ二量体によるシス配列認識の重要性.

    大槻晃史, 鈴木未来子, 勝岡史城, 守田匡伸, 清水律子, 山本雅之

    日本生化学会東北支部 第82回例会

  12. Nrf2-小Maf因子によるシス配列認識の特殊性が酸化ストレス応答において重要である

    大槻晃史, 鈴木未来子, 勝岡史城, 守田匡伸, 清水律子, 山本雅之

    新学術領域研究 酸素生物学 & ダイイングコード

  13. Nrf2A502Y変異はNrf2による生体防御遺伝子の発現誘導を障害する

    大槻晃史, 鈴木未来子, 守田匡伸, 清水律子, 山本雅之

    第87回日本生化学会大会

︎全件表示 ︎最初の5件までを表示

共同研究・競争的資金等の研究課題 9

  1. 環境適応の強靭性を司るエピゲノム制御可変域のシステム生物学的探索

    村谷 匡史, 大槻 晃史, 東谷 篤志, 笹倉 靖徳, 藤田 知道, 安部 智子, 加藤 浩, 鈴木 利貞, 小林 剛, 笹原 信一朗

    2025年4月 ～ 2030年3月

  2. 日本人三世代マルチオミックス解析による非遺伝的DNAメチル化継承の検証

    美辺 詩織, 大槻 晃史

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2026年4月1日 ～ 2029年3月31日

  3. 全長トランスクリプトーム解析を基盤としたNRF2活性化がんの悪性化機構と治療標的探索

    大槻 晃史

    2026年4月 ～ 2029年3月

  4. NRF2標的遺伝子の活性化に基づく疾患リスク層別化法の開発

    山本雅之、大槻晃史、日高高徳

    2025年4月 ～ 2027年3月

  5. シングルセルゲノミクスとPheWAS解析による歯周病の個別化医療・予防の確立

    山田 聡, 鈴木 茂樹, 大槻 晃史, 村上 伸也, 梶川 哲宏

    2023年4月 ～ 2026年3月

  6. 高次クロマチン構造変換を介した抗酸化・抗炎症遺伝子制御機構の解明

    大槻 晃史

    2022年4月 ～ 2026年3月

    詳細を見る 詳細を閉じる

    炎症応答は外来刺激に対する生体防御機構として重要であるが、過剰かつ慢性化した炎症は様々な疾患の原因となる。CNC群転写因子NRF2は、生体の酸化ストレス応答に必須の転写因子であり、抗酸化・解毒酵素の発現制御を担うとともに様々な炎症性疾患の病態を緩和させることが知られている。近年のゲノム解析技術の進歩に伴い、様々な細胞・環境においてNRF2が結合するゲノム領域が網羅的に同定されてきたが、それらの多くは遺伝子発現制御における機能が不明であり、標的遺伝子を正確に特定することは極めて難しい。また、NRF2結合サイトに見られる遺伝的バリアントがいかなるメカニズムで標的遺伝子制御に影響を及ぼすかは十分に明らかでない。そこで本研究では、NRF2結合領域に見られるDNA配列を詳細に解析し、さらに標的遺伝子発現制御の際に生じるクロマチン構造を解析することで、エンハンサー・プロモーター間の相互作用を介した標的遺伝子制御機構の解明に挑む。令和5年度までに、ENCODEデータベースに収載されているクロマチン免疫沈降シークエンス (ChIP-Seq) データの解析から、エンハンサー活性を伴うNRF2結合領域をゲノムワイドに同定した。次に、東北メディカル・メガバンク機構のヒト遺伝的バリアントデータベースと比較参照することによって、抗酸化剤応答配列内に存在しNRF2結合能に影響を及ぼす可能性がある一塩基バリアントを抽出、その中から実際に標的遺伝子の発現を著しく減弱させるものを特定した。令和6年度には、NRF2領域と標的遺伝子プロモーターとの間の物理的相互作用を詳細に解析するための予備検討を着実に進めており、実験の条件設定の最適化に取り組んでいる。

  7. sMaf転写因子を中心とした遺伝子発現制御ネットワークの解明

    大槻 晃史

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Early-Career Scientists

    研究機関：Tohoku University

    2019年4月 ～ 2021年3月

    詳細を見る 詳細を閉じる

    sMaf群転写因子は、酸化ストレス応答のマスター転写因子であるNrf2をはじめとするCNC群転写因子とのヘテロ二量体を形成することで、様々な生体防御遺伝子の発現を誘導する。またそれ以外にも、sMaf群転写因子自身がホモ二量体化することによって標的遺伝子の抑制性制御に関わっていると考えられている。細胞内では、sMafおよびCNC両因子存在比に応じて、様々な組み合わせの二量体が形成されうるが、それぞれの二量体がどのような標的遺伝子の発現を選択的に制御するかという点は十分に明らかではない。既に申請者らのグループでは、sMaf因子を欠失したマウス線維芽細胞（sMaf三重欠失細胞）株において、リンカーペプチドで結合した二量体を強制的に発現させる実験系の構築に成功しており、CNC群転写因子Nrf2とsMafとの二量体リンカー分子を用いた機能解析を行っていた。 そこで申請者らは、同様の実験系を用いてsMafホモ二量体を選択的に発現させることで、sMafホモ二量体が制御する標的遺伝子を明らかにしようと試みた。これまでに、sMaf群因子のひとつであるMafG同士をリンカーペプチドで結合させた分子（MafGホモ二量体）を発現させるためのプラスミドベクター構築を作成し、得られた構築をsMaf三重欠失細胞株に強制発現させることで、sMafレスキュー細胞株の樹立および実験系の構築を進めている。当初の予定よりレスキュー細胞系の樹立に時間がかかっており、計画当初の予定よりやや遅れている。

  8. 転写因子GATA3を中心とした顎顔面形成シグナルネットワークの解明 競争的資金

    大槻 晃史

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up

    研究種目：Grant-in-Aid for Research Activity Start-up

    2016年8月 ～ 2018年3月

    詳細を見る 詳細を閉じる

    Zinc finger型転写因子GATA3は胎生期の様々な臓器・組織に発現し、これらの発生や形態形成に重要な役割を果たしている。今回我々は、胎生期の顎顔面領域におけるGATA3の発現プロファイルを詳細に解析するとともに、GATA3低発現マウスが口蓋形態の異常および腎臓の形成不全を呈し、出生後早期に死亡することを明らかにした。また、酵母人工染色体 (YAC) トランスジェニックマウスの解析から、Gata3遺伝子座の周囲約662kbの領域が、胎生期の鰓弓および尿管原基におけるGATA3の発現に重要な役割を担っていることを明らかにした。

  9. Nrf2と小Maf二量体による協調的な生体防御遺伝子発現制御の解明 競争的資金

    大槻 晃史

    2015年4月 ～ 2016年3月

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    CNC (cap ’n’ collar) 群転写因子とMaf (v-maf musculoaponeurotic fibrosarcoma oncogene) 群転写因子は、様々な遺伝子発現制御に関わっている。Mafホモ二量体は、MARE (Maf認識配列) を認識し、CNC-小Mafヘテロ二量体は、ARE (抗酸化剤応答配列)またはCsMBE (CNC-小Maf結合配列)と呼ばれる配列を認識する。両者は良く似た配列であるが、5’末端がわずかに異なっている。CNC群転写因子Nrf2と小Maf因子からなるヘテロ二量体は酸化ストレスや親電子性物質に対する様々な生体防御遺伝子の発現を誘導することが知られている。Nrf2によるARE/CsMBE認識には502番目に位置するアラニン残基（A）が重要であり、これをチロシン（Y）に置換した変異体（Nrf2(A502Y)）は、MARE配列に対する親和性をもつ。 本研究では、Nrf2変異体ノックインマウスを樹立し、表現型解析と高速シークエンサーで得られたデータの情報科学的解析を行った。その結果、Nrf2(A502Y)変異マウスでは、グルタチオン合成や過酸化水素の消去といった、親電子性物質誘導的なNrf2標的遺伝子の発現が著しく減弱していることが明らかになった。また、発現が減弱した遺伝子の近傍にはNrf2(A502Y)結合が見られなかった。この解析を通じて、ARE/CsMBEとMAREモチーフとの根本的な違いがマウス個体レベルで明らかになり、Nrf2が認識するDNA配列のわずかな違いが、生体の酸化ストレス応答において重要であることを明らかにした。

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担当経験のある科目(授業) 6

  1. 医化学実習　東北大学

  2. 医化学　東北医科薬科大学

  3. 生体分子分析化学　東北大学

  4. 医化学実習　東北医科薬科大学

  5. 基礎化学実習　東北医科薬科大学

  6. 基礎化学　東北医科薬科大学

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