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Atsushi Yokoyama

Section

Graduate School of Medicine

Job title

Associate Professor

Degree

博士（農学） (The University of Tokyo)

researchmap

https://researchmap.jp/7000006957

J-GLOBAL ID

201401004178002892

e-Rad No.

20572332

Research History 8

2021/04 - Present

Tohoku University　Graduate School of Medicine　Associate Professor
2013/04 - 2021/03

Tohoku University　Graduate School of Medicine　Assistant Professor
2012/07 - 2013/03

University of Tokyo　Institute of Molecular and Cellular Biosciences　Assistant Professor
2011/05 - 2012/06

University of Tokyo　Institute of Molecular and Cellular Biosciences　Specially Appointed Assistant Professor (Full time)
2010/04 - 2011/04

University of Tokyo　Institute of Molecular and Cellular Biosciences　Specially Appointed Researcher/Fellow (Full time)
2009/04 - 2010/03

Japan Science and Technology Agency　ERATO　Researcher
2007/04 - 2009/03

Japan Society for the Promotion of Science　Research Fellowship for Young Scientists
2007/11 - 2008/01

Institute of Genetics and Molecular and Cellular Biology (IGBMC)　Visiting researcher

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Education 3

University of Tokyo　Graduate School of Agricultural and Life Sciences　Department of Biotechnology

2006/04 - 2009/03
University of Tokyo　Graduate School of Agricultural and Life Sciences　Department of Applied Biological Chemistry

2003/04 - 2006/03
University of Tokyo　Department of Applied Biological Chemistry

1999/04 - 2003/03

Committee Memberships 3

日本アンドロロジー学会　評議委員

2026 -
日本内分泌学会　評議委員

2026 -
日本ステロイドホルモン学会　評議委員

2025 -

Professional Memberships 8

日本レチノイド研究会

2022/08 -
日本アンドロロジー学会

2022/03 -
日本ステロイドホルモン学会

2022/02 -
日本糖尿病学会

2020/12 -
The Japan Endocrine Society

2018/04 -
THE JAPANESE BIOCHEMICAL SOCIETY

2016/05 -
JAPAN SOCIETY FOR BIOSCIENCE, BIOTECHNOLOGY, AND AGROCHEMISTRY

2008/02 -
THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

2007/07 -

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Research Interests 19

高血圧
メタボリックシンドローム
β細胞
糖毒性
糖尿病性腎症
糖尿病
エピジェネティクス
ヒストン修飾
翻訳後修飾
組織特異的転写制御
複合体精製
質量分析
プロテオミクス
遺伝子発現制御
クロマチン
内分泌学
nuclear receptor
epigenome
transcription

Research Areas 5

Life sciences / Nutrition and health science /
Life sciences / Molecular biology /
Life sciences / Metabolism and endocrinology /
Life sciences / Sports science /
Life sciences / Pathobiochemistry /

Awards 7

令和6年度医学部・医学系研究科教育貢献賞（学部教育）

2025/03　東北大学大学院医学系研究科
医学研究奨励賞

2024/09　公益財団法人艮陵医学振興会
令和5年度医学部・医学系研究科教育貢献賞（大学院教育）

2024/03　東北大学大学院医学系研究科
安斎記念糖尿病研究奨励賞

2023/11　公益財団法人艮陵医学振興会
武藤賞

2022/10　日本レチノイド研究会
優秀ポスター賞

2017/08　第3回Neo Vitamin D Workshop
船越龍・鶴代賞

2009/12

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Papers 72

Identification and characterization of a novel Plakoglobin-binding protein highly expressed in the testes. International-journal

Miyu Yamashita, Kotone Teshima, Mizuki Higuchi, Riko Yamada, Shun Sawatsubashi, Atsushi Yokoyama, Ikuo Tomioka, Kei-Ichiro Ishiguro, Hiroaki Konishi

Biochimica et biophysica acta. Molecular cell research　120170-120170　2026/06/11

DOI： 10.1016/j.bbamcr.2026.120170 　

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1700020L24Rik was originally identified as one of the numerous mouse genes transcriptionally regulated by MEIOSIN (Meiosis initiator), but the function of its gene product has remained unknown. The human homolog of 1700020L24Rik is C17orf50, and both genes are highly expressed in the testes. In this study, we report that the protein encoded by 1700020L24Rik/C17orf50 is a Plakoglobin-binding protein. As its binding promotes the degradation of Plakoglobin, we named it Plakoglobin binding and degradation factor (PGBDF). PGBDF binds to the armadillo repeat of Plakoglobin via an α-helical region formed by approximately ten amino acids. PGBDF overexpression in cultured cells reduces the levels of Plakoglobin and induces cell aggregation accompanied by morphological changes. PGBDF localizes to both the cytoplasm and nucleus, and its subcellular distribution is regulated by phosphorylation. The inhibition of PGBDF phosphorylation by LiCl treatment promotes its cytoplasmic translocation, suggesting regulation by GSK3β and Wnt signaling. In mouse testes, PGBDF is predominantly expressed in interstitial regions. These findings suggest that PGBDF may contribute to the regulation of Plakoglobin levels and adhesion properties in testicular cells.
β-Nicotinamide mononucleotide preserves muscle strength in septic male mice. International-journal Peer-reviewed

Mari Saida, Noritaka Saeki, Hiroshi Sakai, Jun Iwanami, Atsushi Yokoyama, Shun Sawatsubashi, Motoi Kanagawa, Norio Sato, Yuuki Imai

Scientific reports　16　(1)　2026/03/13

DOI： 10.1038/s41598-026-43172-w 　

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Sepsis remains a leading cause of mortality and long-term disability, with survivors frequently developing intensive care unit-acquired weakness (ICU-AW) as part of post-intensive care syndrome. To identify a nutritional therapy for ICU-AW, we investigated the mechanisms underlying sepsis-induced skeletal muscle dysfunction using a cecal slurry-induced sepsis mouse model. Although body weight and skeletal muscle mass recovered 14 days after sepsis induction, muscle strength remained impaired, accompanied by persistent mitochondrial abnormalities. Transcriptomic analysis revealed that the pathways termed the 'sirtuin signaling pathway' and 'mitochondrial dysfunction' significantly enriched and Sirt3, a major mitochondrial nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, was downregulated. Biochemical analyses confirmed increased acetylated lysine of mitochondrial proteins in septic muscle tissue. Among these proteins, mass spectrometry detected several proteins in the acetylated band, including multiple complex I subunits. Whether these are direct SIRT3 targets remains to be determined. Knockdown of Sirt3 in C2C12 myotubes impaired mitochondrial respiration, whereas treatment with β-nicotinamide mononucleotide (β-NMN) partially rescued energy production. In vivo, acute-phase administration of β-NMN preserved mitochondrial morphology and skeletal muscle strength without altering muscle mass. These findings demonstrate that sepsis induces mitochondrial dysfunction and persistent muscle weakness associated with Sirt3 downregulation, and highlights β-NMN supplementation as a promising NAD⁺-targeted therapeutic strategy for mitigating ICU-AW.
Period 1 (PER1): A novel glucocorticoid-responsive gene involved in cortisol-induced proliferation of androgen-independent human prostate cancer DU145 cells. International-journal Peer-reviewed

Shuko Hata, Hiroki Shimada, Atsushi Yokoyama, Yasuhiro Nakamura

Histology and histopathology　40　(12)　1941-1948　2025/12

DOI： 10.14670/HH-18-912 　

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Glucocorticoid receptor (GR) has been implicated in prostate carcinoma and possibly involved in cancer growth and progression. Therefore, in this study, we examined whether the genes involved in cell proliferation regulation were induced by cortisol in androgen-independent human prostate cancer DU145 cells. Gene expression profiling of the DU145 cell pathway was conducted using the RT2 Profile PCR Array System, quantitative reverse transcriptase polymerase chain reaction, and immunoblot analysis. These analyses demonstrated that the expression level of Period 1 (PER1), a gene associated with an organism's biological clock and involved in anti-apoptosis and cell growth, was markedly increased in DU145 cells treated with dexamethasone (DEX). In addition, analysis using short hairpin RNA demonstrated that products of PER1 were involved in the DEX-induced proliferation of DU145 cells. Therefore, PER1 is considered a glucocorticoid-responsive gene that regulates DU145 cell proliferation induced by GR stimulation, thus potentially playing an important role in GR-related androgen-independent human prostate cancer.
HER2 Interactome Profiling Reveals MARCKS as a Candidate Marker Associated with Aggressive Breast Cancer. International-journal Peer-reviewed

Atsushi Yokoyama, Shun Sawatsubashi, Akiko Ebata, Yasuhiro Miki, Yuri Otsubo, Takashi Suzuki

Cancers　17　(17)　2025/09/02

DOI： 10.3390/cancers17172882 　

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Background/Objectives: HER2, a critical diagnostic marker and therapeutic target in breast cancer, is a membrane receptor that forms diverse signaling complexes, the constituents of which have not been fully characterized in actual breast cancer tissues. Methods: In this study, we applied the Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) method, originally developed to explore transcription factor complexes, to identify the complexes formed by HER2 in HER2-positive breast cancer specimens. Results: Through our approach, we successfully identified multiple complex components, including MARCKS, a novel HER2-interacting partner, which we verified using both proximal ligation assay in cultured cells and immunohistochemistry in tissue sections. TCGA analysis further revealed that high MARCKS expression significantly correlates with ER negativity, as confirmed by multivariate analysis, suggesting its potential role as a prognostic indicator in aggressive breast cancer subtypes. Conclusions: These results demonstrate the capability of RIME to elucidate interactomes of membrane proteins such as HER2 in clinical tissue specimens. Furthermore, this study highlights its broader applicability beyond nuclear proteins, underscoring its potential for discovering novel prognostic and diagnostic clinical markers in diverse cancer types.
Erratum: Myofiber androgen receptor increases muscle strength mediated by a skeletal muscle splicing variant of Mylk4. International-journal

Iori Sakakibara, Yuta Yanagihara, Koichi Himori, Takashi Yamada, Hiroshi Sakai, Yuichiro Sawada, Hirotaka Takahashi, Noritaka Saeki, Hiroyuki Hirakawa, Atsushi Yokoyama, So-Ichiro Fukada, Tatsuya Sawasaki, Yuuki Imai

iScience　28　(6)　112643-112643　2025/06/20

DOI： 10.1016/j.isci.2025.112643 　

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[This corrects the article DOI: 10.1016/j.isci.2021.102303.].
A CRISPR-based high-throughput screening system identifies bromodomain inhibitors as transcriptional suppressors of CYP11B1. International-journal Peer-reviewed

Ryo Ito, Taichi Nakano, Akira Sugawara, Atsushi Yokoyama

Biochemical and biophysical research communications　762　151779-151779　2025/05/05

DOI： 10.1016/j.bbrc.2025.151779 　

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CYP11B1 encodes steroid 11β-hydroxylase, the final rate-limiting enzyme for cortisol biosynthesis in the adrenal cortex. Excessive cortisol production is a hallmark of Cushing's disease (CD). While direct enzymatic inhibitors have been explored, achieving specificity remains a challenge due to the high homology between CYP11B1 and CYP11B2, highlighting transcriptional suppression of CYP11B1 as an alternative therapeutic strategy. To identify transcriptional regulators of CYP11B1, we generated genome-edited H295R adrenal cells carrying a luciferase reporter knocked into the endogenous CYP11B1 locus. Using this reporter cell line, we established a high-throughput screening (HTS) platform and screened a focused chemical library targeting epigenetic-related factors, given the importance of epigenetic mechanisms in gene regulation. Among eight candidate compounds identified, we focused on JQ1, a bromodomain inhibitor. JQ1 significantly suppressed Forskolin-induced CYP11B1 promoter activity and mRNA expression without causing cytotoxicity, suggesting the involvement of epigenetic readers in the transcriptional regulation of steroidogenic genes. Furthermore, the reporter-based HTS platform developed here, when combined with our previously established CYP11B2-luciferase system, may facilitate the identification of compounds that selectively modulate adrenal steroidogenic pathways. These findings provide a foundation for the development of novel transcription-targeted therapies for CD.
副腎におけるKCNJ5変異体を標的とした原発性アルドステロン症の新規創薬

尾坪優李, 島田洋樹, 横山敦, 中村保宏, 菅原明

日本内分泌学会雑誌　100　(1)　362-362　2024/05
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
ESS2 controls prostate cancer progression through recruitment of chromodomain helicase DNA binding protein 1. International-journal Peer-reviewed

Sayuri Takahashi, Ichiro Takada, Kenichi Hashimoto, Atsushi Yokoyama, Tohru Nakagawa, Makoto Makishima, Haruki Kume

Scientific reports　13　(1)　12355-12355　2023/07/31

DOI： 10.1038/s41598-023-39626-0 　

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Molecular targeted therapy using poly (ADP-ribose) polymerase inhibitors has improved survival in patients with castration-resistant prostate cancer (CRPC). However, this approach is only effective in patients with specific genetic mutations, and additional drug discovery targeting epigenetic modulators is required. Here, we evaluated the involvement of the transcriptional coregulator ESS2 in prostate cancer. ESS2-knockdown PC3 cells dramatically inhibited proliferation in tumor xenografts in nude mice. Microarray analysis revealed that ESS2 regulated mRNA levels of chromodomain helicase DNA binding protein 1 (CHD1)-related genes and other cancer-related genes, such as PPAR-γ, WNT5A, and TGF-β, in prostate cancer. ESS2 knockdown reduced nuclear factor (NF)-κB/CHD1 recruitment and histone H3K36me3 levels on the promoters of target genes (TNF and CCL2). In addition, we found that the transcriptional activities of NF-κB, NFAT and SMAD2/3 were enhanced by ESS2. Tamoxifen-inducible Ess2-knockout mice showed delayed prostate development with hypoplasia and disruption of luminal cells in the ventral prostate. Overall, these findings identified ESS2 acts as a transcriptional coregulator in prostate cancer and ESS2 can be novel epigenetic therapeutic target for CRPC.
Primary aldosteronism and obstructive sleep apnea: the strong ties between them. International-journal Peer-reviewed

Akira Sugawara, Hiroki Shimada, Yuri Otsubo, Takumi Kouketsu, Atsushi Yokoyama

Hypertension research : official journal of the Japanese Society of Hypertension　46　(7)　1712-1713　2023/05/09

DOI： 10.1038/s41440-023-01303-0 　
CYP11B2とKCNJ5変異体を標的とした原発性アルドステロン症の新規創薬

尾坪優李, 横山敦, 島田洋樹, 中村保宏, 菅原明

ACTH RELATED PEPTIDES　34　64-65　2023/03
Publisher: 間脳・下垂体・副腎系研究会
ISSN： 1340-4512
YM750, an ACAT Inhibitor, Acts on Adrenocortical Cells to Inhibit Aldosterone Secretion Due to Depolarization. International-journal Peer-reviewed

Hiroki Shimada, Shuko Hata, Yuto Yamazaki, Yuri Otsubo, Ikuko Sato, Kazue Ise, Atsushi Yokoyama, Takashi Suzuki, Hironobu Sasano, Akira Sugawara, Yasuhiro Nakamura

International journal of molecular sciences　23　(21)　2022/10/24

DOI： 10.3390/ijms232112803 　

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Primary aldosteronism (PA) is considered the most common form of secondary hypertension, which is associated with excessive aldosterone secretion in the adrenal cortex. The cause of excessive aldosterone secretion is the induction of aldosterone synthase gene (CYP11B2) expression by depolarization of adrenocortical cells. In this study, we found that YM750, an Acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, acts on adrenocortical cells to suppress CYP11B2 gene expression and aldosterone secretion. YM750 inhibited the induction of CYP11B2 gene expression by KCl stimulation, but not by angiotensin II and forskolin stimulation. Interestingly, YM750 did not inhibit KCl-stimulated depolarization via an increase in intracellular calcium ion concentration. Moreover, ACAT1 expression was relatively abundant in the zona glomerulosa (ZG) including these CYP11B2-positive cells. Thus, YM750 suppresses CYP11B2 gene expression by suppressing intracellular signaling activated by depolarization. In addition, ACAT1 was suggested to play an important role in steroidogenesis in the ZG. YM750 suppresses CYP11B2 gene expression and aldosterone secretion in the adrenal cortex, suggesting that it may be a potential therapeutic agent for PA.
Transcriptional coregulator Ess2 controls survival of post-thymic CD4+ T cells through the Myc and IL-7 signaling pathways. International-journal Peer-reviewed

Ichiro Takada, Shinya Hidano, Sayuri Takahashi, Kaori Yanaka, Hidesato Ogawa, Megumi Tsuchiya, Atsushi Yokoyama, Shingo Sato, Hiroki Ochi, Tohru Nakagawa, Takashi Kobayashi, Shinichi Nakagawa, Makoto Makishima

The Journal of biological chemistry　298　(9)　102342-102342　2022/08/03

DOI： 10.1016/j.jbc.2022.102342 　

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Ess2, also known as Dgcr14, is a transcriptional co-regulator of CD4+ T cells. Ess2 is located in a chromosomal region, the loss of which has been associated with 22q11.2 deletion syndrome (22q11DS), which causes heart defects, skeletal abnormalities and immunodeficiency. However, the specific association of Ess2 with 22q11DS remains unclear. To elucidate the role of Ess2 in T-cell development, we generated Ess2 floxed (Ess2fl/fl) and CD4+ T cell-specific Ess2 KO (Ess2ΔCD4/ΔCD4) mice using the Cre/loxP system. Interestingly, Ess2ΔCD4/ΔCD4 mice exhibited reduced naïve T-cell numbers in the spleen, while the number of thymocytes (CD4-CD8-, CD4+CD8+, CD4+CD8- and CD4-CD8+) in the thymus remained unchanged. Furthermore, Ess2ΔCD4/ΔCD4 mice had decreased NKT cells and increased γδT cells in the thymus and spleen. A genome-wide expression analysis using RNA-seq revealed that Ess2 deletion alters the expression of many genes in CD4 single-positive thymocytes, including genes related to the immune system and Myc target genes. In addition, Ess2 enhanced the transcriptional activity of c-Myc. Some genes identified as Ess2 targets in mice show expressional correlation with ESS2 in human immune cells. Moreover, Ess2ΔCD4/ΔCD4 naïve CD4+ T cells did not maintain survival in response to IL-7. Our results suggest that Ess2 plays a critical role in post thymic T-cell survival through the Myc and IL-7 signaling pathways.
IRF2BP2 is a novel HNF4α co-repressor: Its role in gluconeogenic gene regulation via biochemically labile interaction. International-journal Peer-reviewed

Takumi Kouketsu, Rina Monma, Yuri Miyairi, Shun Sawatsubashi, Hiroki Shima, Kazuhiko Igarashi, Akira Sugawara, Atsushi Yokoyama

Biochemical and biophysical research communications　615　81-87　2022/05/18

DOI： 10.1016/j.bbrc.2022.04.133 　

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Hepatocyte nuclear factor 4α (HNF4α) has essential roles in controlling the expression of a variety of genes involved in key metabolic pathways, including gluconeogenesis in the liver. The mechanistic and physiological significance of peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) for HNF4α-mediated transcriptional activation models for gluconeogenic genes is well characterized. However, the transcriptional repression of HNF4α for those genes remains to be examined. In this study, we applied novel proteomic techniques to evaluate the interactions of HNF4α, including those with biochemically labile binding proteins. Based upon our experiments, we identified interferon regulatory factor 2 binding protein 2 (IRF2BP2) as a novel HNF4α co-repressor. This interaction could not be detected by conventional immunoprecipitation. IRF2BP2 repressed the transcriptional activity of HNF4α dependent on its E3 ubiquitin ligase activity. Deficiency of the IRF2BP2 gene in HepG2 cells induced gluconeogenic genes comparable to that of forskolin-treated wild-type HepG2 cells. Together, these results suggest that IRF2BP2 represents a novel class of nuclear receptor co-regulator.
The physiological and pathophysiological roles of carbohydrate response element binding protein in the kidney. Invited Peer-reviewed

Atsushi Yokoyama, Susumu Suzuki, Koji Okamoto, Akira Sugawara

Endocrine journal　69　(6)　605-612　2022/04/26

DOI： 10.1507/endocrj.EJ22-0083 　

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Glucose is not only the energy fuel for most cells, but also the signaling molecule which affects gene expression via carbohydrate response element binding protein (ChREBP), a Mondo family transcription factor. In response to high glucose conditions, ChREBP regulates glycolytic and lipogenic genes by binding to carbohydrate response elements (ChoRE) in the regulatory region of its target genes, thus elucidating the role of ChREBP for converting excessively ingested carbohydrates to fatty acids as an energy storage in lipogenic tissues such as the liver and adipose tissue. While the pathophysiological roles of ChREBP for fatty liver and obesity in these tissues are well known, much of the physiological and pathophysiological roles of ChREBP in other tissues such as the kidney remains unclear despite its high levels of expression in them. This review will thus highlight the roles of ChREBP in the kidney and briefly introduce the latest research results that have been reported so far.
Identification and Functional Characterization of a Novel Androgen Receptor Coregulator, EAP1. International-journal Peer-reviewed

Atsushi Yokoyama, Takumi Kouketsu, Yuri Otsubo, Erika Noro, Shun Sawatsubashi, Hiroki Shima, Ikuro Satoh, Sadafumi Kawamura, Takashi Suzuki, Kazuhiko Igarashi, Akira Sugawara

Journal of the Endocrine Society　5　(11)　bvab150　2021/11/01

DOI： 10.1210/jendso/bvab150 　

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The androgen receptor (AR) plays an essential role in the development of prostate cancer, and androgen-deprivation therapy is used as a first-line treatment for prostate cancer. However, under androgen-deprivation therapy, castration-resistant prostate cancer inevitably arises, suggesting that the interacting transcriptional coregulators of AR are promising targets for developing novel therapeutics. In this study, we used novel proteomic techniques to evaluate the AR interactome, including biochemically labile binding proteins, which might go undetected by conventional purification methods. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, we identified enhanced at puberty 1 (EAP1) as a novel AR coregulator, whereas its interaction with AR could not be detected under standard biochemical conditions. EAP1 enhanced the transcriptional activity of AR via the E3 ubiquitin ligase activity, and its ubiquitination substrate proteins included AR and HDAC1. Furthermore, in prostate cancer specimens, EAP1 expression was significantly correlated with AR expression as well as a poor prognosis of prostate cancer. Together, these results suggest that EAP1 is a novel AR coregulator that promotes AR activity and potentially plays a role in prostate cancer progression.
The usefulness of angiotensin-(1-7) and des-Arg9-bradykinin as novel biomarkers for metabolic syndrome. International-journal Peer-reviewed

Akira Sugawara, Hiroki Shimada, Yuri Otsubo, Takumi Kouketsu, Susumu Suzuki, Atsushi Yokoyama

Hypertension research : official journal of the Japanese Society of Hypertension　44　(8)　1034-1036　2021/05/27

DOI： 10.1038/s41440-021-00671-9 　
Myofiber androgen receptor increases muscle strength mediated by a skeletal muscle splicing variant of Mylk4. International-journal Peer-reviewed

Iori Sakakibara, Yuta Yanagihara, Koichi Himori, Takashi Yamada, Hiroshi Sakai, Yuichiro Sawada, Hirotaka Takahashi, Noritaka Saeki, Hiroyuki Hirakawa, Atsushi Yokoyama, So-Ichiro Fukada, Tatsuya Sawasaki, Yuuki Imai

iScience　24　(4)　102303-102303　2021/04/23

DOI： 10.1016/j.isci.2021.102303 　

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Androgens have a robust effect on skeletal muscles to increase muscle mass and strength. The molecular mechanism of androgen/androgen receptor (AR) action on muscle strength is still not well known, especially for the regulation of sarcomeric genes. In this study, we generated androgen-induced hypertrophic model mice, myofiber-specific androgen receptor knockout (cARKO) mice supplemented with dihydrotestosterone (DHT). DHT treatment increased grip strength in control mice but not in cARKO mice. Transcriptome analysis by RNA-seq, using skeletal muscles obtained from control and cARKO mice treated with or without DHT, identified a fast-type muscle-specific novel splicing variant of Myosin light-chain kinase 4 (Mylk4) as a target of AR in skeletal muscles. Mylk4 knockout mice exhibited decreased maximum isometric torque of plantar flexion and passive stiffness of myofibers due to reduced phosphorylation of Myomesin 1 protein. This study suggests that androgen-induced skeletal muscle strength is mediated with Mylk4 and Myomesin 1 axis.
膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

横山敦, 野呂英理香, 岡本好司, 松澤拓郎, 吉川雄朗, 島弘季, 五十嵐和彦, 菅原明

日本内分泌学会雑誌　97　(1)　319-319　2021/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
PCA3 controls chromatin organization and p53 signal activation by regulating LAP2α-lamin A complexes. International-journal Peer-reviewed

Saya Ito, Takashi Ueda, Atsushi Yokoyama, Atsuko Fujihara, Fumiya Hongo, Osamu Ukimura

Cancer gene therapy　29　(3-4)　358-368　2021/03/23

DOI： 10.1038/s41417-021-00314-8 　

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Prostate cancer antigen 3 (PCA3) is a prostate cancer-specific long noncoding RNA (lncRNA). Here, we report that lncRNA PCA3 plays a role in prostate cancer progression that is mediated by nucleoplasmic lamins. PCA3 interacts with the C-terminal region of lamina-associated polypeptide (LAP) 2α. The C-terminal region of LAP2α includes tumor suppressor protein retinoblastoma (pRb)- and lamin-binding domains, and it is necessary for the regulation and stabilization of the nucleoplasmic pool of lamin A. PCA3 inhibits the interaction of LAP2α with lamin A through binding with the C-terminus of LAP2α. The level of nucleoplasmic lamin A/C is increased by knockdown of PCA3. Together, the level of LAP2α within the nucleus is increased by PCA3 knockdown. In PCA3 knockdown cells, the levels of HP1γ, trimethylation of Lys9 on histone H3 (H3K9me3), and trimethylation of Lys36 on histone H3 (H3K36me3) are upregulated. In contrast, trimethylation of Lys4 on histone H3 (H3K4me3) is downregulated. We further demonstrate that activation of the p53 signaling pathway and cell cycle arrest are promoted in the absence of PCA3. These findings support a unique mechanism in which prostate cancer-specific lncRNA controls chromatin organization via regulation of the nucleoplasmic pool of lamins. This proposed mechanism suggests that cancer progression may be mediated by nuclear lamins.
The establishment of a novel high-throughput screening system using RNA-guided genome editing to identify chemicals that suppress aldosterone synthase expression. International-journal Peer-reviewed

Ryo Ito, Masanobu Morita, Taichi Nakano, Ikuko Sato, Atsushi Yokoyama, Akira Sugawara

Biochemical and biophysical research communications　534　672-679　2021/01/01

DOI： 10.1016/j.bbrc.2020.11.020 　

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Aldosterone is synthesized in the adrenal by the aldosterone synthase CYP11B2. Although the control of CYP11B2 expression is important to maintain the mineral homeostasis, its overexpression induced by the depolarization-induced calcium (Ca2+) signaling activation has been reported to increase the synthesis of aldosterone in primary aldosteronism (PA). The drug against PA focused on the suppression of CYP11B2 expression has not yet been developed, since the molecular mechanism of CYP11B2 transcriptional regulation activated via Ca2+ signaling remains unclear. To address the issue, we attempted to reveal the mechanism of the transcriptional regulation of CYP11B2 using chemical screening. We generated a cell line by inserting Nanoluc gene as a reporter into CYP11B2 locus in H295R adrenocortical cells using the CRSPR/Cas9 system, and established the high-throughput screening system using the cell line. We then identified 9 compounds that inhibited the CYP11B2 expression induced by potassium-mediated depolarization from the validated compound library (3399 compounds). Particularly, tacrolimus, an inhibitor of phosphatase calcineurin, strongly suppressed the CYP11B2 expression even at 10 nM. These results suggest that the system is effective in identifying drugs that suppress the depolarization-induced CYP11B2 expression. Our screening system may therefore be a useful tool for the development of novel medicines against PA.
Comparative proteomic analysis to identify the novel target gene of angiotensin II in adrenocortical H295R cells. Peer-reviewed

Ryo Ito, Hiroki Shima, Koji Masuda, Ikuko Sato, Hiroki Shimada, Atsushi Yokoyama, Katsuhiko Shirahige, Kazuhiko Igarashi, Akira Sugawara

Endocrine journal　68　(4)　441-450　2020/12/26

DOI： 10.1507/endocrj.EJ20-0144 　

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Angiotensin II (Ang II) is a well-known peptide that maintains the balance of electrolytes in the higher vertebrates. Ang II stimulation in the adrenal gland induces the synthesis of mineralocorticoids, mainly aldosterone, through the up-regulation of aldosterone synthase (CYP11B2) gene expression. Additionally, it has been reported that Ang II activates multiple signaling pathways such as mitogen-activated protein kinase (MAPK) and Ca2+ signaling. Although Ang II has various effects on the cellular signaling in the adrenal cells, its biological significance, except for the aldosterone synthesis, is still unclear. In this study, we attempted to search the novel target gene(s) of Ang II in the human adrenal H295R cells using a proteomic approach combined with stable isotopic labeling using amino acid in cell culture (SILAC). Interestingly, we found that Ang II stimulation elevated the expression of phosphofructokinase type platelet (PFKP) in both protein and mRNA levels. Moreover, transactivation of PFKP by Ang II was dependent on extracellular-signal-regulated kinase (ERK) 1/2 activation. Finally, we observed that Ang II treatment facilitated glucose uptake in the H295R cells. Taken together, we here identified PFKP as a novel target gene of Ang II, indicating that Ang II not only stimulates steroidogenesis but also affects glucose metabolism.
Publisher Correction: Partial proteasomal degradation of Lola triggers the male-to-female switch of a dimorphic courtship circuit (Nature Communications, (2019), 10, 1, (166), 10.1038/s41467-018-08146-1)

Kosei Sato, Hiroki Ito, Atsushi Yokoyama, Gakuta Toba, Daisuke Yamamoto

Nature Communications　11　(1)　2020/12/01
Publisher: Nature Research
DOI： 10.1038/s41467-020-14881-1 　

ISSN： 2041-1723
Mechanisms of osteoprotective actions of estrogens

Shigeaki Kato, Shun Sawatsubashi, Atsushi Yokoyama, Takashi Nakamura, Alexander Kouzmenko

Encyclopedia of Bone Biology　503-523　2020/06/26
Publisher: Elsevier
CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma. International-journal Peer-reviewed

Kiyohiro Ando, Verna Cázares-Ordoñez, Makoto Makishima, Atsushi Yokoyama, Yusuke Suenaga, Hiroki Nagase, Shinichi Kobayashi, Takehiko Kamijo, Tsugumichi Koshinaga, Satoshi Wada

Journal of oncology　2020　2752417-2752417　2020

DOI： 10.1155/2020/2752417 　

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Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human malignancies, including neuroblastoma. Recently, we reported that CHK1i, PF-477736, induced a p53-mediated DNA damage response. As a result, the cancer cells were able to repair DNA damage and became less sensitive to CHK1i. In this study, we discovered that PF-477736 increased expression of MDM2 oncogene along with CHK1i-induced replication defects in neuroblastoma NB-39-nu cells. A mass spectrometry analysis of protein binding to MDM2 in the presence of CHK1i identified the centrosome-associated family protein 131 (CEP131), which was correlated with unfavorable prognosis of neuroblastoma patients. We revealed that MDM2 was associated with CEP131 protein degradation, whereas overexpression of CEP131 accelerated neuroblastoma cell growth and exhibited resistance to CHK1i-induced replication defects. Thus, these findings may provide a future therapeutic strategy against centrosome-associated oncogenes involving CEP131 as a target in neuroblastoma.
Expression and pathophysiological significance of carbohydrate response element binding protein (ChREBP) in the renal tubules of diabetic kidney. Peer-reviewed

Suzuki S, Yokoyama A, Noro E, Aoki S, Shimizu K, Shimada H, Sugawara A

Endocrine journal　67　(3)　335-345　2019/12
Publisher: Japan Endocrine Society
DOI： 10.1507/endocrj.EJ19-0133 　

ISSN： 0918-8959

eISSN： 1348-4540
Effects of Adipocyte-derived Factors on the Adrenal Cortex. Peer-reviewed

Shimada H, Noro E, Suzuki S, Sakamoto J, Sato I, Parvin R, Yokoyama A, Sugawara A

Current molecular pharmacology　13　(1)　2-6　2019/10
Publisher: Bentham Science Publishers Ltd.
DOI： 10.2174/1874467212666191015161334 　

ISSN： 1874-4672

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Background and Objective: Obesity is highly complicated by hypertension and hyperglycemia.In particular, it has been proposed that obesity-related hypertension is caused by adipocyte-derivedfactors that are recognized as undetermined proteins secreted from adipocytes. Adipocyte-derived factorshave been known to be related to aldosterone secretion in the adrenal gland. So far, Wnt proteins,CTRP-1, VLDL, LDL, HDL and leptin have been demonstrated to stimulate aldosterone secretion. Incontrast, it has not yet been clarified whether adipocyte-derived factors also affect adrenal cortisol secretion. Methods and Results: In the present study, we investigated the effect of adipocyte-derived factors oncortisol synthase gene CYP11B1 mRNA expression in vitro study using adrenocortical carcinomaH295R cells and mouse fibroblast 3T3-L1cells. Interestingly, adipocyte-derived factors were demonstratedto have the ability to stimulate CYP11B1 mRNA expression. Conclusion: Since CYP11B1 is well known as a limiting enzyme of cortisol synthesis, our study suggeststhat adipocyte-derived factors may stimulate cortisol secretion, as well as aldosterone secretion.Taken together, adipocyte-derived factors may be the cause of metabolic syndrome due to their stimulatingeffects on aldosterone/cortisol secretion. Therefore, the innovation of novel drugs against themmay possibly be a new approach against metabolic syndrome.
ゲノム編集を利用したくる病型点変異導入ビタミンD受容体の機能解析

沢津橋俊, 横山敦, 上甲裕大, 松本俊夫, 福本誠二

日本生化学会大会プログラム・講演要旨集　92回　[2T07a-04]　2019/09
Publisher: (公社)日本生化学会
膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

横山敦, 野呂英理香, 松澤拓郎, 吉川雄朗, 島弘季, 五十嵐和彦, 菅原明

日本生化学会大会プログラム・講演要旨集　92回　[3T15m-04]　2019/09
Publisher: (公社)日本生化学会
Transglutaminase-mediated cross-linking of WDR54 regulates EGF receptor-signaling. International-journal Peer-reviewed

Akane Maeda, Tasuku Nishino, Ryota Matsunaga, Atsushi Yokoyama, Hiroshi Suga, Toshiki Yagi, Hiroaki Konishi

Biochimica et biophysica acta. Molecular cell research　1866　(2)　285-295　2019/02

DOI： 10.1016/j.bbamcr.2018.11.009 　

ISSN： 0167-4889

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WDR54 is a member of the WD40 repeat (WDR) domain-containing protein family that was recently identified as a novel oncogene in colorectal cancer. However, the molecular mechanism of WDR54 and its functional association with other molecules related to tumor cell growth are unknown. Here, we show that WDR54 can be cross-linked by the action of transglutaminase (TG) 2, which enhances the activation of EGF receptor-mediated signaling pathway. The most carboxyl-terminal WD domain was required for cross-linking. In addition, lysine 280 in WDR54, also in this WD domain, was an important residue for both cross-linking and ubiquitination. Cross-linked WDR54 was found in vesicles aggregated at the plasma membrane. The activated EGF receptor was co-localized with this vesicle, and the internalization of the EGF receptor into the cytosol was sustained. As a result, Erk activity in response to EGF stimulation was enhanced. Furthermore, the growth of the cells lacking WDR54 expression generated by genome editing was delayed compared with that in wild-type cells. Because TG2 is also has been proposed to activate the EGF receptor-signaling and proliferation of tumor cells, WDR54 might have a functional relationship with the EGF receptor and TG2. Our study on the mechanism of biological function of WDR54 may provide rationale for the design and development of a cancer drug based on inhibiting the post-translational modification of this oncogene product.
Partial proteasomal degradation of Lola triggers the male-to-female switch of a dimorphic courtship circuit Peer-reviewed

Kosei Sato, Hiroki Ito, Atsushi Yokoyama, Gakuta Toba, Daisuke Yamamoto

Nature Communications　10　(1)　2019/01/11
Publisher: Springer Science and Business Media LLC
DOI： 10.1038/s41467-018-08146-1 　

eISSN： 2041-1723

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Abstract InDrosophila, some neurons develop sex-specific neurites that contribute to dimorphic circuits for sex-specific behavior. As opposed to the idea that the sexual dichotomy in transcriptional profiles produced by a sex-specific factor underlies such sex differences, we discovered that the sex-specific cleavage confers the activity as a sexual-fate inducer on the pleiotropic transcription factor Longitudinals lacking (Lola). Surprisingly, Fruitless, another transcription factor with a master regulator role for courtship circuitry formation, directly binds to Lola to protect its cleavage in males. We also show that Lola cleavage involves E3 ubiquitin ligase Cullin1 and 26S proteasome. Our work adds a new dimension to the study of sex-specific behavior and its circuit basis by unveiling a mechanistic link between proteolysis and the sexually dimorphic patterning of circuits. Our findings may also provide new insights into potential causes of the sex-biased incidence of some neuropsychiatric diseases and inspire novel therapeutic approaches to such disorders.
Endogenous purification of NR4A2 (Nurr1) identified poly(ADP-ribose) polymerase 1 as a prime coregulator in human adrenocortical H295R cells Peer-reviewed

Erika Noro, Atsushi Yokoyama, Makoto Kobayashi, Hiroki Shimada, Susumu Suzuki, Mari Hosokawa, Tomohiro Takehara, Rehana Parvin, Hiroki Shima, Kazuhiko Igarashi, Akira Sugawara

International Journal of Molecular Sciences　19　(5)　2018/05/08
Publisher: MDPI AG
DOI： 10.3390/ijms19051406 　

ISSN： 1422-0067 1661-6596
Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells Peer-reviewed

Rehana Parvin, Erika Noro, Akiko Saito-Hakoda, Hiroki Shimada, Susumu Suzuki, Kyoko Shimizu, Hiroyuki Miyachi, Atsushi Yokoyama, Akira Sugawara

PPAR Research　2018　5346272　2018/04/23
Publisher: Hindawi Limited
DOI： 10.1155/2018/5346272 　

ISSN： 1687-4765 1687-4757
The reduction of heparan sulphate in the glomerular basement membrane does not augment urinary albumin excretion Peer-reviewed

Satoshi Aoki, Akiko Saito-Hakoda, Takeo Yoshikawa, Kyoko Shimizu, Kiyomi Kisu, Susumu Suzuki, Kiyoshi Takagi, Shuji Mizumoto, Shuhei Yamada, Toin H. Van Kuppevelt, Atsushi Yokoyama, Taiji Matsusaka, Hiroshi Sato, Sadayoshi Ito, Akira Sugawara

Nephrology Dialysis Transplantation　33　(1)　26-33　2018/01/01
Publisher: Oxford University Press
DOI： 10.1093/ndt/gfx218 　

ISSN： 1460-2385 0931-0509
High glucose stimulates expression of aldosterone synthase (CYP11B2) and secretion of aldosterone in human adrenal cells Peer-reviewed

Hiroki Shimada, Naotaka Kogure, Erika Noro, Masataka Kudo, Kaori Sugawara, Ikuko Sato, Kyoko Shimizu, Makoto Kobayashi, Dai Suzuki, Rehana Parvin, Takako Saito-Ito, Akira Uruno, Akiko Saito-Hakoda, William E. Rainey, Sadayoshi Ito, Atsushi Yokoyama, Akira Sugawara

FEBS OPEN BIO　7　(9)　1410-1421　2017/09

DOI： 10.1002/2211-5463.12277 　

ISSN： 2211-5463
Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure Peer-reviewed

Dai Suzuki, Akiko Saito-Hakoda, Ryo Ito, Kyoko Shimizu, Rehana Parvin, Hiroki Shimada, Erika Noro, Susumu Suzuki, Ikuma Fujiwara, Hiroyuki Kagechika, William E. Rainey, Shigeo Kure, Sadayoshi Ito, Atsushi Yokoyama, Akira Sugawara

PLOS ONE　12　(8)　e0181055　2017/08

DOI： 10.1371/journal.pone.0181055 　

ISSN： 1932-6203
Effects of Retinoids on Vasculatures Peer-reviewed

Rehana Parvin, Akiko Saito-Hakoda, Susumu Suzuki, Erika Noro, Hiroki Shimada, Atsushi Yokoyama, Akira Sugawara

Journal of Endocrinology and Thyroid Research　2　(3)　1-5　2017/07/06
Publisher: Juniper Publishers
DOI： 10.19080/jetr.2017.02.555587 　

ISSN： 2573-2188
A ubiquitin-proteasome inhibitor bortezomib suppresses the expression of CYP11B2, a key enzyme of aldosterone synthesis Peer-reviewed

Ryo Ito, Ikuko Sato, Tadayuki Tsujita, Atsushi Yokoyama, Akira Sugawara

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　489　(1)　21-28　2017/07

DOI： 10.1016/j.bbrc.2017.05.109 　

ISSN： 0006-291X

eISSN： 1090-2104
Role of NeuroD1 on the negative regulation of Pomc expression by glucocorticoid Peer-reviewed

Rehana Parvin, Akiko Saito-Hakoda, Hiroki Shimoda, Kyoko Shimizu, Erika Noro, Yasumasa Iwasaki, Ken Fujiwara, Atsushi Yokoyama, Akira Sugawara

PLOS ONE　12　(4)　e0175435　2017/04

DOI： 10.1371/journal.pone.0175435 　

ISSN： 1932-6203
Biochemical analysis of histone succinylation Peer-reviewed

Atsushi Yokoyama, Shogo Katsura, Akira Sugawara

Biochemistry Research International　2017　8529404　2017
Publisher: Hindawi Limited
DOI： 10.1155/2017/8529404 　

ISSN： 2090-2255 2090-2247
Hydroxylation of methylated DNA by TET1 in chondrocyte differentiation of C3H10T1/2 cells Peer-reviewed

Ryo Ito, Hiroki Shimada, Kengo Yazawa, Ikuko Sato, Yuuki Imai, Akira Sugawara, Atsushi Yokoyama

Biochemistry and Biophysics Reports　5　134-140　2016/03/01
Publisher: Elsevier
DOI： 10.1016/j.bbrep.2015.11.009 　

ISSN： 2405-5808
Versatile function of the circadian protein CIPC as a regulator of Erk activation Peer-reviewed

Ryota Matsunaga, Tasuku Nishino, Atsushi Yokoyama, Akio Nakashima, Ushio Kikkawa, Hiroaki Konishi

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　469　(3)　377-383　2016/01

DOI： 10.1016/j.bbrc.2015.11.117 　

ISSN： 0006-291X

eISSN： 1090-2104
Effects of RXR Agonists on Cell Proliferation/Apoptosis and ACTH Secretion/Pomc Expression Peer-reviewed

Akiko Saito-Hakoda, Akira Uruno, Atsushi Yokoyama, Kyoko Shimizu, Rehana Parvin, Masataka Kudo, Takako Saito-Ito, Ikuko Sato, Naotaka Kogure, Dai Suzuki, Hiroki Shimada, Takeo Yoshikawa, Ikuma Fujiwara, Hiroyuki Kagechika, Yasumasa Iwasaki, Shigeo Kure, Sadayoshi Ito, Akira Sugawara

PLOS ONE　10　(12)　e0141960　2015/12

DOI： 10.1371/journal.pone.0141960 　

ISSN： 1932-6203
The roles of histone modifier complexes in tissue-specific transcriptional regulation

Yokoyama, A., Sugawara, A.

Seikagaku. The Journal of Japanese Biochemical Society　87　(5)　2015
Retinoic acid receptor-a up-regulates proopiomelanocortin gene expression in AtT20 corticotroph cells Peer-reviewed

Akira Uruno, Akiko Saito-Hakoda, Atsushi Yokoyama, Naotaka Kogure, Ken Matsuda, Rehana Parvin, Kyoko Shimizu, Ikuko Sato, Masataka Kudo, Takeo Yoshikawa, Hiroyuki Kagechika, Yasumasa Iwasaki, Sadayoshi Ito, Akira Sugawara

ENDOCRINE JOURNAL　61　(11)　1105-1114　2014/11

DOI： 10.1507/endocrj.EJ14-0115 　

ISSN： 0918-8959

eISSN： 1348-4540
High-Glucose Stimulates Aldosterone Synthase Gene (CYP11B2) Expression Via the Induction of T-Type Calcium Channels in H295R Cells Peer-reviewed

Naotaka Kogure, Ken Matsuda, Akira Uruno, Kaori Sugawara, Ikuko Sato, Kyoko Shimizu, Rehana Parvin, Takeo Yoshikawa, Masataka Kudo, Akiko Saito-Hakoda, Ryo Ito, Atsushi Yokoyama, Sadayoshi Ito, Akira Sugawara

ENDOCRINE REVIEWS　35　(3)　2014/06

ISSN： 0163-769X

eISSN： 1945-7189
Effects of RXR Agonist HX630 on Pomc Promoter Activity and in Vivo Tumor Formation Peer-reviewed

Akiko Saito-Hakoda, Akira Uruno, Kyoko Shimizu, Naotaka Kogure, Rehana Parvin, Ikuko Sato, Ikuma Fujiwara, Hiroyuki Kagechika, Yasumasa Iwasaki, Atsushi Yokoyama, Sadayoshi Ito, Akira Sugawara

ENDOCRINE REVIEWS　35　(3)　2014/06

ISSN： 0163-769X

eISSN： 1945-7189
Generation of a Stable H295R Cell Line Expressing 11beta-Hydroxylase Gene Promoter and the Effect of High-Glucose on Its Expression Peer-reviewed

Atsushi Yokoyama

ENDOCRINE REVIEWS　35　(3)　2014/06

ISSN： 0163-769X
The Innovation of a Novel Drug Screening System for the Inhibitors of Aldosterone Synthase Gene (CYP11B2) Expression Peer-reviewed

Atsushi Yokoyama

ENDOCRINE REVIEWS　35　(3)　2014/06

ISSN： 0163-769X
Identification of Myelin Transcription Factor 1 (MyT1) as a Subunit of the Neural Cell Type-specific Lysine-specific Demethylase 1 (LSD1) Complex Peer-reviewed

Atsushi Yokoyama, Katsuhide Igarashi, Tetsuya Sato, Kiyoshi Takagi, Maky Otsuka, Yurina Shishido, Takashi Baba, Ryo Ito, Jun Kanno, Yasuyuki Ohkawa, Ken-ichirou Morohashi, Akira Sugawara

JOURNAL OF BIOLOGICAL CHEMISTRY　289　(26)　18152-18162　2014/06

DOI： 10.1074/jbc.M114.566448 　

ISSN： 0021-9258

eISSN： 1083-351X
Angiotensin II receptor blockers differentially affect CYP11B2 expression in human adrenal H295R cells Peer-reviewed

Ken Matsuda, Akira Uruno, Naotaka Kogure, Kaori Sugawara, Hiroki Shimada, Masahiro Nezu, Takako Saito-Ito, Yuko Iki, Masataka Kudo, Kyoko Shimizu, Ikuko Sato, Takeo Yoshikawa, Fumitoshi Satoh, Ryo Ito, Atsushi Yokoyama, William E. Rainey, Akiko Saito-Hakoda, Sadayoshi Ito, Akira Sugawara

MOLECULAR AND CELLULAR ENDOCRINOLOGY　383　(1-2)　60-68　2014/03

DOI： 10.1016/j.mce.2013.12.004 　

ISSN： 0303-7207
Angiotensin II receptor blockers differentially affect CYP11B2 expression in human adrenal H295R cells Peer-reviewed

Ken Matsuda, Akira Uruno, Naotaka Kogure, Kaori Sugawara, Hiroki Shimada, Masahiro Nezu, Takako Saito-Ito, Yuko Iki, Masataka Kudo, Kyoko Shimizu, Ikuko Sato, Takeo Yoshikawa, Fumitoshi Satoh, Ryo Ito, Atsushi Yokoyama, William E. Rainey, Akiko Saito-Hakoda, Sadayoshi Ito, Akira Sugawara

MOLECULAR AND CELLULAR ENDOCRINOLOGY　383　(1-2)　60-68　2014/03

DOI： 10.1016/j.mce.2013.12.004 　

ISSN： 0303-7207
ARB affects nicotine-induced gene expression profile in human coronary artery endothelial cells Peer-reviewed

Atsushi Yokoyama

World Journal of Hypertension.　4　(1)　7-14　2014/02

DOI： 10.5494/wjh.v4.i1.7. 　
TET3-OGT interaction increases the stability and the presence of OGT in chromatin Peer-reviewed

Ryo Ito, Shogo Katsura, Hiroki Shimada, Hikaru Tsuchiya, Masashi Hada, Tomoko Okumura, Akira Sugawara, Atsushi Yokoyama

GENES TO CELLS　19　(1)　52-65　2014/01

DOI： 10.1111/gtc.12107 　

ISSN： 1356-9597

eISSN： 1365-2443
Is Heparan Sulfate in the Glomerular Basement Membrane Necessary for the Etiology of Diabetic Nephropathy? Peer-reviewed

Atsushi Yokoyama

Biomolecular Research & Therapeutics　3　(e127)　2014/01

DOI： 10.4172/2167-7956.1000e127 　
Identification of Posttranslational Modifications in Peroxisome Proliferator-Activated Receptor gamma Using Mass Spectrometry Peer-reviewed

Shogo Katsura, Tomoko Okumura, Ryo Ito, Akira Sugawara, Atsushi Yokoyama

PPAR RESEARCH　2014　(468925)　2014

DOI： 10.1155/2014/468925 　

ISSN： 1687-4757

eISSN： 1687-4765
The androgen receptor in health and disease Peer-reviewed

Takahiro Matsumoto, Matomo Sakari, Maiko Okada, Atsushi Yokoyama, Sayuri Takahashi, Alexander Kouzmenko, Shigeaki Kato

Annual Review of Physiology　75　201-224　2013/02/10

DOI： 10.1146/annurev-physiol-030212-183656 　

ISSN： 0066-4278 1545-1585
The Androgen Receptor in Health and Disease Peer-reviewed

Takahiro Matsumoto, Matomo Sakari, Maiko Okada, Atsushi Yokoyama, Sayuri Takahashi, Alexander Kouzmenko, Shigeaki Kato

ANNUAL REVIEW OF PHYSIOLOGY, VOL 75　75　201-224　2013

DOI： 10.1146/annurev-physiol-030212-183656 　

ISSN： 0066-4278
JMJD5, a Jumonji C (JmjC) Domain-containing Protein, Negatively Regulates Osteoclastogenesis by Facilitating NFATc1 Protein Degradation Peer-reviewed

Min-Young Youn, Atsushi Yokoyama, Sally Fujiyama-Nakamura, Fumiaki Ohtake, Ken-ichi Minehata, Hisataka Yasuda, Takeshi Suzuki, Shigeaki Kato, Yuuki Imai

JOURNAL OF BIOLOGICAL CHEMISTRY　287　(16)　12994-13004　2012/04

DOI： 10.1074/jbc.M111.323105 　

ISSN： 0021-9258
GlcNAcylation of histone H2B facilitates its monoubiquitination. International-journal Peer-reviewed

Ryoji Fujiki, Waka Hashiba, Hiroki Sekine, Atsushi Yokoyama, Toshihiro Chikanishi, Saya Ito, Yuuki Imai, Jaehoon Kim, Housheng Hansen He, Katsuhide Igarashi, Jun Kanno, Fumiaki Ohtake, Hirochika Kitagawa, Robert G Roeder, Myles Brown, Shigeaki Kato

Nature　480　(7378)　557-60　2011/11/27

DOI： 10.1038/nature10656 　

ISSN： 0028-0836

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Chromatin reorganization is governed by multiple post-translational modifications of chromosomal proteins and DNA. These histone modifications are reversible, dynamic events that can regulate DNA-driven cellular processes. However, the molecular mechanisms that coordinate histone modification patterns remain largely unknown. In metazoans, reversible protein modification by O-linked N-acetylglucosamine (GlcNAc) is catalysed by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). However, the significance of GlcNAcylation in chromatin reorganization remains elusive. Here we report that histone H2B is GlcNAcylated at residue S112 by OGT in vitro and in living cells. Histone GlcNAcylation fluctuated in response to extracellular glucose through the hexosamine biosynthesis pathway (HBP). H2B S112 GlcNAcylation promotes K120 monoubiquitination, in which the GlcNAc moiety can serve as an anchor for a histone H2B ubiquitin ligase. H2B S112 GlcNAc was localized to euchromatic areas on fly polytene chromosomes. In a genome-wide analysis, H2B S112 GlcNAcylation sites were observed widely distributed over chromosomes including transcribed gene loci, with some sites co-localizing with H2B K120 monoubiquitination. These findings suggest that H2B S112 GlcNAcylation is a histone modification that facilitates H2BK120 monoubiquitination, presumably for transcriptional activation.
Multiple post-translational modifications in hepatocyte nuclear factor 4α. International-journal Peer-reviewed

Atsushi Yokoyama, Shogo Katsura, Ryo Ito, Waka Hashiba, Hiroki Sekine, Ryoji Fujiki, Shigeaki Kato

Biochemical and biophysical research communications　410　(4)　749-53　2011/07/15

DOI： 10.1016/j.bbrc.2011.06.033 　

ISSN： 0006-291X

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To investigate the role of post-translational modifications (PTMs) in the hepatocyte nuclear factor 4α (HNF4α)-mediated transcription, we took a comprehensive survey of PTMs in HNF4α protein by mass-spectrometry and identified totally 8 PTM sites including newly identified ubiquitilation and acetylation sites. To assess the impact of identified PTMs in HNF4α-function, we introduced point mutations at the identified PTM sites and, tested transcriptional activity of the HNF4α. Among the point-mutations, an acetylation site at lysine 458 was found significant in the HNF4α-mediated transcriptional control. An acetylation negative mutant at lysine 458 showed an increased transcriptional activity by about 2-fold, while an acetylation mimic mutant had a lowered transcriptional activation. Furthermore, this acetylation appeared to be fluctuated in response to extracellular nutrient conditions. Thus, by applying an comprehensive analysis of PTMs, multiple PTMs were newly identified in HNF4α and unexpected role of an HNF4α acetylation could be uncovered.
Nuclear receptor coregulators merge transcriptional coregulation with epigenetic regulation Invited Peer-reviewed

Shigeaki Kato, Atsushi Yokoyama, Ryoji Fujiki

TRENDS IN BIOCHEMICAL SCIENCES　36　(5)　272-281　2011/05

DOI： 10.1016/j.tibs.2011.01.001 　

ISSN： 0968-0004
Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment Peer-reviewed

Julie M. Quach, Emma C. Walker, Elizabeth Allan, Melissa Solano, Atsushi Yokoyama, Shigeaki Kato, Natalie A. Sims, Matthew T. Gillespie, T. John Martin

JOURNAL OF BIOLOGICAL CHEMISTRY　286　(6)　4186-4198　2011/02

DOI： 10.1074/jbc.M110.178251 　

ISSN： 0021-9258
Regulated histone methyltransferase and demethylase complexes in the control of genes by nuclear receptors Invited Peer-reviewed

A. Yokoyama, R. Fujiki, F. Ohtake, S. Kato

Cold Spring Harbor Symposia on Quantitative Biology　76　165-173　2011

DOI： 10.1101/sqb.2011.76.010736 　

ISSN： 0091-7451
細胞内発現タンパク質の精製と解析 Invited

横山敦, 加藤茂明

メディカルバイオ（オーム社）　7　(6)　41-44　2010/11
Publisher:
ISSN： 1881-9354
KIAA1718 is a histone demethylase that erases repressive histone methyl marks. International-journal Peer-reviewed

Atsushi Yokoyama, Yosuke Okuno, Toshihiro Chikanishi, Waka Hashiba, Hiroki Sekine, Ryoji Fujiki, Shigeaki Kato

Genes to cells : devoted to molecular & cellular mechanisms　15　(8)　867-73　2010/08

DOI： 10.1111/j.1365-2443.2010.01424.x 　

ISSN： 1356-9597

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The methylation states of histone lysine residues are regarded as significant epigenetic marks governing transcriptional regulation. A number of histone demethylases containing a jumonji C (JmjC) domain have been recognized; however, their properties remain to be investigated. Here, we show that KIAA1718, a PHF2/PHF8 subfamily member, possesses histone demethylase activity specific for H3K9 and H3K27, transcriptionally repressive histone marks. Biochemical purification of the KIAA1718 interactants reveals that KIAA1718 forms complexes with several factors including KAP1, a transcriptional co-activator. Consistent with these findings, KIAA1718 shows a transcriptional activation function in the chromatin context. Thus, our study identifies KIAA1718 as a histone demethylase for repressive methyl marks and shows that it is involved in transcriptional activation.
Glucose-induced expression of MIP-1 genes requires O-GlcNAc transferase in monocytes. International-journal Peer-reviewed

Toshihiro Chikanishi, Ryoji Fujiki, Waka Hashiba, Hiroki Sekine, Atsushi Yokoyama, Shigeaki Kato

Biochemical and biophysical research communications　394　(4)　865-70　2010/04/16

DOI： 10.1016/j.bbrc.2010.02.167 　

ISSN： 0006-291X

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O-glycosylation has emerged as an important modification of nuclear proteins, and it appears to be involved in gene regulation. Recently, we have shown that one of the histone methyl transferases (MLL5) is activated through O-glycosylation by O-GlcNAc transferase (OGT). Addition of this monosaccharide is essential for forming a functional complex. However, in spite of the abundance of OGT in the nucleus, the impact of nuclear O-glycosylation by OGT remains largely unclear. To address this issue, the present study was undertaken to test the impact of nuclear O-glycosylation in a monocytic cell line, THP-1. Using a cytokine array, MIP-1alpha and -1beta genes were found to be regulated by nuclear O-glycosylation. Biochemical purification of the OGT interactants from THP-1 revealed that OGT is an associating partner for distinct co-regulatory complexes. OGT recruitment and protein O-glycosylation were observed at the MIP-1alpha gene promoter; however, the known OGT partner (HCF-1) was absent when the MIP-1alpha gene promoter was not activated. From these findings, we suggest that OGT could be a co-regulatory subunit shared by functionally distinct complexes supporting epigenetic regulation.
Phosphorylation of WSTF by MAPK is required for the regulation of VDR-mediated transcription by WINAC

Atsushi Yokoyama

ENDOCRINE JOURNAL　2010
Transrepressive function of TLX requires the histone demethylase LSD1 Peer-reviewed

Atsushi Yokoyama, Shinichiro Takezawa, Roland Schuele, Hirochika Kitagawa, Shigeaki Kato

MOLECULAR AND CELLULAR BIOLOGY　28　(12)　3995-4003　2008/06

DOI： 10.1128/MCB.02030-07 　

ISSN： 0270-7306
核内受容体転写因子群の単離・同定・機能解析 Invited

藤木亮次, 中村(藤山)沙理, 横山敦, 加藤茂明

生体の科学第５９巻第３号（（財）金原一郎記念医学医療振興財団／医学書院）　59　(3)　242-247　2008
Publisher:
DOI： 10.11477/mf.2425100176 　

ISSN： 0370-9531
核内ステロイド受容体・環境ホルモン研究 Invited

大竹史明, 高田伊知郎, 藤木亮次, 横山敦, 加藤茂明

細胞・培地活用ハンドブック（羊土社）　2008
Muc4 is required for activation of ErbB2 in signet ring carcinoma cell lines Peer-reviewed

Atsushi Yokoyama, Bin-Hai Shi, Takayuki Kawai, Hiroaki Konishi, Ryota Andoh, Hiroyuki Tachikawa, Sayoko Ihara, Yasuhisa Fukui

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　355　(1)　200-203　2007/03

DOI： 10.1016/j.bbrc.2007.01.133 　

ISSN： 0006-291X
シグナル伝達機構：２．メッセンジャーと受容体 Invited

横山敦

細胞の世界（西村書店）　2005

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Misc. 61

RIME法を用いたタンパク質間相互作用解析とその応用 Invited

横山敦

内分泌に関する最新情報（公益財団法人山口内分泌疾患研究振興財団）　2025/05
CYP11B2とKCNJ5変異を標的とした原発性アルドステロン症の新規創薬

尾坪優李, 島田洋樹, 横山敦, 中村保宏, 菅原明

日本内分泌学会雑誌　101　(1)　2025

ISSN： 0029-0661
タバコ煙成分によるアンドロゲン受容体活性化メカニズムの解析 Invited

横山敦

令和6年度喫煙科学研究財団年報研究年報（公益財団法人喫煙科学研究財団）　44-48　2025
RIME法を用いたタンパク質間相互作用解析 Invited

横山敦

組織細胞化学 2024　143-150　2024/07
副腎皮質におけるアルドステロン過剰分泌の分子機序と創薬の試み

島田洋樹, 尾坪優李, 横山敦, 菅原明, 中村保宏

日本臨床内分泌病理学会学術総会プログラム・抄録集　28th　2024
タバコ煙成分によるアンドロゲン受容体活性化メカニズムの解析 Invited

横山敦

令和5年度喫煙科学研究財団年報研究年報（公益財団法人喫煙科学研究財団）　2024
ステロイドホルモン研究における組織学的アプローチ

鈴木貴, 山崎有人, 岩渕英里奈, 横山敦, 高木清司, 三木康宏

組織細胞化学 2023　197-206　2023/07
新たなアンドロゲン受容体制御因子を求めて Invited

横山敦, 纐纈拓海, 菅原明

日本アンドロロジー学会ニュースレター　26　2023/04
脂肪細胞由来未知因子による副腎CYP11B2発現誘導機序の解明

島田洋樹, 尾坪優李, 横山敦, 菅原明, 中村保宏

間脳・下垂体・副腎系研究会プログラム・抄録集(Web)　34th　2023
核内受容体新規転写共役因子の探索

横山敦, 纐纈拓海, 尾坪優李, 沢津橋俊, 島弘季, 佐藤郁郎, 川村貞文, 鈴木貴, 五十嵐和彦, 菅原明

日本アンドロロジー学会総会記事　41st　2022

ISSN： 0918-6239
アンドロゲン受容体新規転写共役因子の探索

横山敦, 纐纈拓海, 尾坪優李, 沢津橋俊, 島弘季, 佐藤郁郎, 川村貞文, 鈴木貴, 五十嵐和彦, 菅原明

日本アンドロロジー学会総会記事　41st　2022

ISSN： 0918-6239
アルドステロン合成酵素(CYP11B2)とKCNJ5変異体を標的とした原発性アルドステロン症の新規創薬

尾坪優李, 横山敦, 島田洋樹, 中村保宏, 菅原明

日本内分泌学会雑誌　98　(1)　2022

ISSN： 0029-0661
CYP11B2とKCNJ5変異体を標的とした原発性アルドステロン症の新規治療薬の開発

尾坪優李, 五十嵐萌, 横山敦, 島田洋樹, 中村保宏, 菅原明

日本臨床内分泌病理学会学術総会プログラム・抄録集　25th　2021
未知の脂肪細胞由来因子による副腎CYP11B2発現誘導機序の解明

坂本純, 島田洋樹, 横山敦, 菅原明

日本高血圧学会総会プログラム・抄録集　42回　225-225　2019/10
Publisher: (NPO)日本高血圧学会
脂肪細胞由来の未知のアルドステロン合成酵素(CYP11B2)発現誘導因子の探索

島田洋樹, 佐藤郁子, 坂本純, 横山敦, 菅原明

日本高血圧学会総会プログラム・抄録集　42回　226-226　2019/10
Publisher: (NPO)日本高血圧学会
CYP11B2をターゲットとした原発性アルドステロン症の新規創薬の試み

星啓太, 横山敦, 佐藤郁子, 島田洋樹

日本高血圧学会総会プログラム・抄録集　42回　228-228　2019/10
Publisher: (NPO)日本高血圧学会
軟骨細胞の分化におけるIGF-1遺伝子のエピジェネティック制御と成長ホルモンの作用

菅原明, 横山敦

成長科学協会研究年報　(42)　113　2019/10
肝臓におけるHnf4αを介した糖新生遺伝子の転写メカニズムの解明

門間里奈, 横山敦, 島弘季, 五十嵐和彦, 菅原明

日本生化学会大会プログラム・講演要旨集　92回　[1T13a-06]　2019/09
Publisher: (公社)日本生化学会
ゲノム編集を利用したくる病型点変異導入ビタミンD受容体の機能解析

沢津橋俊, 横山敦, 上甲裕大, 松本俊夫, 福本誠二

日本生化学会大会プログラム・講演要旨集　92回　[2T07a-04]　2019/09
Publisher: (公社)日本生化学会
膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

横山敦, 野呂英理香, 松澤拓郎, 吉川雄朗, 島弘季, 五十嵐和彦, 菅原明

日本生化学会大会プログラム・講演要旨集　92回　[3T15m-04]　2019/09
Publisher: (公社)日本生化学会
内分泌代謝とエピゲノム膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

横山敦, 野呂英理香, 菅原明

日本内分泌学会雑誌　95　(1)　206-206　2019/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
アカデミア発創薬による糖尿病性腎症の新規治療薬の開発

鈴木歩, 野呂英理香, 清水恭子, 横山敦, 菅原明

日本内分泌学会雑誌　95　(1)　333-333　2019/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
アルドステロン合成酵素の転写制御因子の同定

野呂英理香, 横山敦, 小林真, 島田洋樹, 西澤翔輝, 門間里奈, 鈴木歩, 島弘季, 五十嵐和彦, 菅原明

日本内分泌学会雑誌　95　(1)　439-439　2019/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
CYP11B2を標的とした原発性アルドステロン症の新規創薬の試み

星啓太, 伊藤亮, 佐藤郁子, 坂本純, 島田洋樹, 横山敦, 菅原明

日本内分泌学会雑誌　95　(1)　501-501　2019/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
アンジオテンシンIIはFXRのリガンド活性化と相乗的な効果をもたらす

島田洋樹, 野呂英理香, 佐藤郁子, 鈴木歩, 坂本純, 横山敦, 菅原明

日本内分泌学会雑誌　94　(4)　1596-1596　2018/12
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子のRIME法を用いた探索

野呂英理香, 横山敦, 小暮直敬, 鈴木歩, 清水恭子, 島弘季, 五十嵐和彦, 菅原明

日本内分泌学会雑誌　94　(1)　360-360　2018/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
グルコース応答性転写因子ChREBPの腎組織における発現・機能解析

鈴木歩, 野呂英理香, 横山敦, 菅原明

日本内分泌学会雑誌　94　(1)　391-391　2018/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
アンジオテンシンIIはFXRのリガンド活性化と相乗的な効果をもたらす

島田洋樹, 野呂英理香, 佐藤郁子, 鈴木歩, 坂本純, 横山敦, 菅原明

日本内分泌学会雑誌　94　(1)　427-427　2018/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
VIKING法によるノックアウト/ノックイン細胞を用いた比較プロテオーム解析によるビタミンD受容体複合体の探索

沢津橋俊, 横山敦, 上甲裕大, 菅野茂夫, 菅野茂夫, 松本俊夫, 福本誠二

日本分子生物学会年会プログラム・要旨集(Web)　41st　2018
グルコース応答性転写因子ChREBPの機能制御因子の探索

野呂英理香, 横山敦, 小暮直敬, 鈴木歩, 清水恭子, 島弘季, 五十嵐和彦, 菅原明

日本内分泌学会雑誌　93　(1)　363-363　2017/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
炭水化物応答配列結合蛋白(ChREBP)関連遺伝子の探索

鈴木歩, 野呂英理香, 清水恭子, 横山敦, 菅原明

日本内分泌学会雑誌　93　(1)　365-365　2017/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
新たな翻訳後修飾の探索

横山敦, 菅原明

日本生化学会大会プログラム・講演要旨集　89回　[3P-102]　2016/09
Publisher: (公社)日本生化学会
未知の脂肪細胞由来アルドステロン合成酵素(CYP11B2)発現誘導因子の探索

島田洋樹, 伊藤亮, 佐藤恵美子, 伊藤貞嘉, 横山敦, 菅原明

日本高血圧学会総会プログラム・抄録集　39回　331-331　2016/09
Publisher: (NPO)日本高血圧学会
レチノイドX受容体(RXR)アゴニストPA024が副腎CYP11B2発現、アルドステロン分泌および血圧に及ぼす影響

鈴木大, 箱田明子, 伊藤亮, 清水恭子, 小暮直敬, 青木聡, 影近弘之, 呉繁夫, 伊藤貞嘉, 横山敦, 菅原明

日本高血圧学会総会プログラム・抄録集　39回　336-336　2016/09
Publisher: (NPO)日本高血圧学会
軟骨細胞の分化におけるIGF‐1遺伝子のエピジェネティック制御と成長ホルモンの作用

菅原明, 横山敦, 伊藤亮

成長科学協会研究年報　(39)　115　2016/09/01

ISSN： 0386-7617
軟骨細胞の分化におけるIGF‐1遺伝子のエピジェネティック制御と成長ホルモンの作用

菅原明, 横山敦, 伊藤亮

東北医学雑誌　128　(1)　72　2016/06/25

ISSN： 0040-8700
脂肪細胞由来の未知のアルドステロン合成酵素(CYP11B2)発現誘導因子の探索

島田洋樹, 伊藤亮, 佐藤恵美子, 横山敦, 菅原明

日本内分泌学会雑誌　92　(1)　216-216　2016/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
デキサメサゾンによるPOMC遺伝子転写抑制における転写因子NeuroD1の作用

パービン・レハナ, 箱田明子, 島田洋樹, 横山敦, 菅原明

ACTH RELATED PEPTIDES　27　5-5　2016/03
Publisher: 間脳・下垂体・副腎系研究会
ISSN： 1340-4512
レチノイド受容体と内分泌・代謝疾患

菅原明, 宇留野晃, 横山敦, 箱田明子, 影近弘之

日本応用酵素協会誌　(50)　21-24　2016/03
Publisher: (公財)日本応用酵素協会
ISSN： 0913-3348

eISSN： 2434-7914
グルコース応答性転写因子ChREBPの機能制御因子の探索

野呂英理香, 横山敦, 小暮直敬, 清水恭子, 島弘季, 五十嵐和彦, 菅原明

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[3LBA034]-[3LBA034]　2015/12
Publisher: (公社)日本生化学会
組織特異的な転写制御をつかさどるピストン修飾因子複合体

横山敦, 菅原明

生化学　87　(5)　621-624　2015/10/25
Publisher: 日本生化学会
DOI： 10.14952/SEIKAGAKU.2015.870621 　

ISSN： 0037-1017
アルドステロン合成酵素遺伝子の転写制御

横山敦

東北医学雑誌　127　(1)　99　2015/06/25

ISSN： 0040-8700
Pomc遺伝子のグルココルチコイドによるネガティブ・レギュレーションにおけるNeuroD1の関与

パービン・レハナ, 箱田明子, 清水恭子, 宇留野晃, 鈴木大, 青木聡, 島田洋樹, 小暮直敬, 工藤正孝, 岩崎泰正, 伊藤貞嘉, 横山敦, 菅原明

日本内分泌学会雑誌　91　(1)　266-266　2015/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
種々のレチノイドX受容体アゴニストは、AtT20細胞の増殖・アポトーシス・Pomc発現・ACTH分泌に異なる影響を及ぼす

箱田明子, 宇留野晃, 清水恭子, パービン・レハナ, 横山敦, 吉川雄朗, 工藤正孝, 影近弘之, 岩崎泰正, 伊藤貞嘉, 菅原明

日本内分泌学会雑誌　91　(1)　269-269　2015/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
レチノイドX受容体アゴニストPA024が副腎CYP11B2発現・アルドステロン分泌に及ぼす影響の検討

鈴木大, 箱田明子, 清水恭子, パービン・レハナ, 宇留野晃, 青木聡, 佐藤郁子, 島田洋樹, 小暮直敬, 藤原幾磨, 伊藤貞嘉, 影近弘之, 横山敦, 菅原明

日本内分泌学会雑誌　91　(1)　400-400　2015/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
高血糖刺激による副腎アルドステロン合成酵素遺伝子(CYP11B2)発現亢進

小暮直敬, 菅原香織, 工藤正孝, 島田洋樹, 箱田明子, 伊藤亮, 横山敦, 菅原明

糖尿病　58　(Suppl.1)　S-356　2015/04
Publisher: (一社)日本糖尿病学会
ISSN： 0021-437X

eISSN： 1881-588X
高血糖刺激による副腎アルドステロン合成酵素遺伝子(CYP11B2)発現亢進の分子機構

小暮直敬, 菅原香織, 松田謙, 宇留野晃, 佐藤郁子, 清水恭子, レハナ・パービン, 島田洋樹, 吉川雄朗, 工藤正孝, 箱田明子, 伊藤亮, 横山敦, 伊藤貞嘉, 菅原明

日本高血圧学会総会プログラム・抄録集　37回　333-333　2014/10
Publisher: (NPO)日本高血圧学会
アルドステロン合成酵素遺伝子(CYP11B2)をターゲットとした新規創薬

伊藤亮, 島田洋樹, 松田謙, 宇留野晃, 横山敦, 菅原明

日本高血圧学会総会プログラム・抄録集　37回　393-393　2014/10
Publisher: (NPO)日本高血圧学会
高血糖刺激は副腎11β-水酸化酵素遺伝子(CYP11B1)の発現を誘導する

菅原香織, 小暮直敬, 松田謙, 宇留野晃, 佐藤郁子, 清水恭子, レハナ・パービン, 島田洋樹, 吉川雄朗, 工藤正孝, 箱田明子, 伊藤亮, 横山敦, 伊藤貞嘉, 菅原明

日本高血圧学会総会プログラム・抄録集　37回　399-399　2014/10
Publisher: (NPO)日本高血圧学会
HPA系の基礎研究Update 高血糖刺激による副腎11β-水酸化酵素遺伝子(CYP11B1)の発現誘導

菅原香織, 小暮直敬, 宇留野晃, 松田謙, 佐藤郁子, 清水恭子, 工藤正孝, 箱田明子, 島田洋樹, 伊藤亮, 横山敦, 伊藤貞嘉, 菅原明

ACTH RELATED PEPTIDES　25　20-21　2014/03
Publisher: 間脳・下垂体・副腎系研究会
ISSN： 1340-4512
レチノイドX受容体アゴニストHX630によるPomc遺伝子転写抑制機構の解明ならびにin vivo腫瘍抑制効果の検討

箱田明子, 宇留野晃, 清水恭子, 小暮直敬, 佐藤郁子, 藤原幾磨, 影近弘之, 岩崎泰正, 横山敦, 伊藤貞嘉, 菅原明

ACTH RELATED PEPTIDES　25　28-29　2014/03
Publisher: 間脳・下垂体・副腎系研究会
ISSN： 1340-4512
ヒストンH2B脱O‐GlcNAc酵素の分子メカニズムの解明

関根弘樹, 藤木亮次, 橋場和華, 横山敦, 加藤茂明

生化学　ROMBUNNO.4P-0400　2011

ISSN： 0037-1017
生化学的手法による新規ヒストンH2B相互作用因子の同定

橋場和華, 関根弘樹, 横山敦, 近西俊洋, 藤木亮次, 加藤茂明

生化学　ROMBUNNO.1P-0684　2010

ISSN： 0037-1017
核内O‐GlcNAc修飾を介するエピゲノム制御機構の新たな作用点の探索

藤木亮次, 近西俊洋, 橋場和華, 関根弘樹, 横山敦, 加藤茂明

生化学　ROMBUNNO.3W20-5　2010

ISSN： 0037-1017
ヒストン脱メチル化酵素による神経分化制御メカニズムの解析

横山敦, 奥野陽亮, 橋場和華, 関根弘樹, 藤山沙理, 北川浩史, 藤木亮次, 加藤茂明

生化学　ROMBUNNO.1P-0683　2010

ISSN： 0037-1017
ヒストン脱メチル化酵素LSD1による神経分化制御メカニズムの解析

横山敦, 藤山沙理, 北川浩史, 加藤茂明

生化学　ROMBUNNO.3P-680　2009/09/25

ISSN： 0037-1017
核内レセプターと炎症

北川浩史, 横山敦, 加藤茂明

感染・炎症・免疫　39　(1)　14-25　2009/04/10

ISSN： 0387-1010
実験講座核内受容体転写因子群の単離・同定・機能解析

藤木亮次, 中村(藤山)沙理, 横山敦, 加藤茂明

生体の科学　59　(3)　242-247　2008/06/15

DOI： 10.11477/mf.2425100176 　

ISSN： 0370-9531
オーファン核内受容体TLXの転写抑制を介した神経幹細胞未分化維持機構の解明

横山敦, 竹澤慎一郎, 北川浩史, 加藤茂明

生化学　1P-0819　2008

ISSN： 0037-1017
クロマチン構造変換を介した核内受容体転写修飾因子複合体の機能解析

北川浩史, 藤木亮次, 吉村公宏, 大矢博之, 神津円, 岡田麻衣子, 横山敦, 竹澤慎一郎, 加藤茂明

生化学　2W8-3　2007

ISSN： 0037-1017
オーファン核内受容体TLXの,転写共役因子複合体の同定による転写抑制機構の解明

横山敦, 竹澤慎一郎, 北川浩史, 加藤茂明

生化学　2P-0929　2007

ISSN： 0037-1017

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Books and Other Publications 4

ビタミン・バイオファクター総合事典

横山敦, 馬場泰輔, 加藤茂明

朝倉書店　2021/07

ISBN: 9784254102925
Encyclopedia of Bone Biology

Kato S, Sawatsubashi S, Yokoyama A, Nakamura T, Kouzmenko A

Elsevier Inc.　2020
細胞・培地活用ハンドブック

大竹史明, 高田伊知郎, 藤木亮次, 横山敦, 加藤茂明

羊土社　2008
細胞の世界

横山敦

西村書店　2005

Presentations 29

グルコース応答性転写因子ChREBPをターゲットとした糖尿病性腎臓病の新規治療戦略の開発 Invited

横山敦

腎疾患研究AMED支援課題コンソーシアム 2026　2026/09/01
タバコ煙成分によるアンドロゲン受容体制御メカニズムの解析 Invited

横山敦

令和7年度喫煙科学研究財団助成研究発表会　2026/07/17
A nuclear receptor corepressor condensate recruits IRF2BP2 to modulate HNF4α-dependent repression. Invited

ICE2026/JES2026、Symposium 17: Nuclear Receptors: Their Transcription Regulations and Disorders　2026/06/05
タバコ煙成分によるアンドロゲン受容体制御メカニズムの解析

横山敦, 佐藤美桜, 阿部優香, 寒河江向燿, 小林研太郎, 菅原明

日本レチノイド研究会第36回学術集会　2025/10/18
タバコ煙成分によるアンドロゲン受容体制御メカニズムの解析 Invited

横山敦

令和6年度喫煙科学研究財団助成研究発表会　2025/07/18
タバコ煙成分によるアンドロゲン受容体制御メカニズムの解析

横山敦, 阿部優香, 寒河江向燿, 小林研太郎, 菅原明

日本アンドロロジー学会第44回学術大会　2025/06/20
Functional Analysis of Nuclear Receptors and Nutrition-Responsive Transcription Factors in Endocrine/Metabolic Disorders Using Drug Screening. Invited

2024/11/06
タバコ煙抽出液によるアンドロゲン受容体制御メカニズムの解析

横山敦, 阿部優香, 寒河江向燿, 小林研太郎, 菅原明

日本レチノイド研究会第35回学術集会　2024/10/12
Analysis of androgen receptor regulatory mechanisms by tobacco smoke condensates.

Atsushi Yokoyama, Yuka Abe, Koyo Sagae, Kentaro Kobayashi, Akira Sugawara

EMBO Workshop Nuclear Receptors: No Disease is Safe　2024/09/24
Development of an anti-diabetic kidney disease drug by targeting transcriptional activity of carbohydrate responsive element binding protein (ChREBP) Invited

Atsushi Yokoyama

IGBMC seminar　2024/09/20
RIME法を利用したタンパク質間相互作用解析 Invited

横山敦

第49回組織細胞化学講習会　2024/08/09
タバコ煙成分によるアンドロゲン受容体制御メカニズムの解析 Invited

横山敦

令和5年度喫煙科学研究財団助成研究発表会　2024/07/19
タバコ煙成分によるアンドロゲン受容体制御メカニズムの解析

横山敦, 阿部優香, 寒河江向燿, 小林研太郎, 菅原明

日本アンドロロジー学会第43回学術大会　2024/06/08
Identification of a novel androgen receptor coactivator EAP1 involved in prostate cancer prognosis

2022/10/14
Functional regulation of the glucose-responsive transcription factor ChREBP by inflammatory signals. Invited

RIIM 5th Anniversary Symposium program　2022/06/05
核内受容体新規転写共役因子の探索 Invited

横山敦

日本アンドロロジー学会第41回学術大会シンポジウム４次世代研究者シンポジウム　2022/06/04
アンドロゲン受容体新規転写共役因子の探索

横山敦

日本アンドロロジー学会第41回学術大会　2022/06/03
炎症シグナルによるグルコース応答性転写因子ChREBPの機能制御メカニズムの解明

横山敦

第95回日本内分泌学会学術総会　2022/06/02
炎症シグナルによるグルコース応答性転写因子ChREBPの機能制御メカニズムの解明

横山敦

第42回日本内分泌学会東北地方会　2022/04/30
膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索

横山敦

第92回日本生化学会大会　2019/09/20
膵β細胞におけるグルコース応答性転写因子ChREBPの機能制御因子の探索 Invited

横山敦

第92回日本内分泌学会学術総会シンポジウム8 内分泌代謝とエピゲノム　2019/05/09
新たな転写複合体同定の試み Invited

横山敦

第１回次世代生命科学の研究会　2016/08/12
Identification of MyT1 as a subunit of the neural cell-type specific complex International-presentation

横山敦

新学術領域「性差構築の分子基盤」若手集会　2014/12/10
性ホルモン受容体を介した転写制御機構の解明

横山敦

第５回新学術領域「性差構築の分子基盤」領域会議　2014/09/05
組織特異的なヒストン修飾因子複合体の解析

横山敦

第１回疾患エピゲノムコアセンターミニシンポジウム〜未知の生命現象•疾患の解明を目指して〜　2013/10/26
遺伝子発現を制御する新たな翻訳後修飾の探索 Invited

横山敦

第１６回がん・エピゲノム研究会　2013/07/17
遺伝子発現を制御する新たな翻訳後修飾の探索 Invited

横山敦

第4回新学術領域「性差構築の分子基盤」領域会議　2012/10/15
核内受容体HNF4αの翻訳後修飾の網羅的同定

横山敦

日本農芸化学会大会　2012/03/26
オーファン核内受容体TLXの、転写共役因子複合体の同定による転写抑制機構の解明

横山敦

２００７年度東京大学分子細胞生物学研究所所内発表会　2007/11/22

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Industrial Property Rights 2

1,3-ジオキソラン誘導体

菅原明, 横山敦, 鈴木歩, 岩渕好治, 土井隆行

特許第7573272号

Property Type: Patent
１，３ージオキソラン誘導体

菅原明, 横山敦, 鈴木歩, 岩渕好治, 土井隆行

Property Type: Patent

Research Projects 29

腎臓におけるグルコース応答性転写因子ChREBP活性の時空間的パターンの解明

Offer Organization: 公益財団法人鈴木万平糖尿病財団

System: 調査研究助成（B)

2026/04 - 2029/03
グルコース応答性転写因子ChREBPをターゲットとした糖尿病性腎臓病の新規治療戦略の開発

Offer Organization: 国立研究開発法人日本医療研究開発機構

System: 腎疾患実用化研究事業

2024/07 - 2027/03
糖質応答転写因子ChREBPの新規阻害薬を用いた糖尿病性腎臓病の病態解明・制御

菅原明, 岩渕好治, 広川貴次, 横山敦, 沢津橋俊, 岡本好司

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 基盤研究(B)

Institution: 東北大学

2024/04 - 2027/03
新規ChREBP阻害薬の標的遺伝子に対するPerturbシークエンスを用いたNAFLDの病態制御

菅原明, 岩渕好治, 横山敦, 井上淳, 岡本好司

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 挑戦的研究(萌芽)

Institution: 東北大学

2024/06/28 - 2026/03/31
ゲノム編集細胞を用いたグルコース依存的転写制御のライブ観察

横山敦

Offer Organization: 徳島大学先端酵素学研究所

System: 2025年度徳島大学先端酵素学研究所「酵素学研究拠点」共同利用

2025/04 - 2026/03
タバコ煙成分によるアンドロゲン受容体活性化メカニズムの解析

横山敦

Offer Organization: 公益財団法人喫煙科学研究財団

System: 令和5年度喫煙科学研究財団助成研究

2023/04 - 2026/03
グルコース応答性転写因子ChREBPを標的とする糖尿病性腎臓病の新規創薬

Offer Organization: 公益財団法人鈴木謙三記念医科学応用研究財団

System: 令和6年度調査研究助成金

2024/12 - 2025/12
VIKING 法による高効率ゲノム編集を利用した骨格筋におけるアンドロゲン受容体のパイオニア因子の探索

Offer Organization: 徳島大学先端酵素学研究所

System: 2024年度徳島大学先端酵素学研究所「酵素学研究拠点」共同研究

2024/04 - 2025/03
小児骨格筋におけるアンドロゲン受容体の遺伝子制御メカニズムの解明

横山敦

Offer Organization: 公益財団法人成長科学協会

System: 研究助成

2023/09 - 2024/03
VIKING 法による高効率ゲノム編集を利用したパイオニア因子に関するLLPS関連因子のスクリーニング

Offer Organization: 徳島大学先端酵素学研究所

System: 2023年度徳島大学先端酵素学研究所「酵素学研究拠点」共同利用

2023/04 - 2024/03
グルコース応答性転写因子ChREBPの分子機能解析による糖尿病性腎症の病態解明

横山敦

Offer Organization: 一般財団法人代謝異常治療研究基金

System: 令和５年度代謝異常治療研究基金

2023/04 - 2024/03
骨格筋におけるアンドロゲン受容体のパイオニア因子の同定・解析

横山敦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業基盤研究(C)

Category: 基盤研究(C)

Institution: 東北大学

2021/04 - 2024/03

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超高齢化社会を迎えた本邦における健康寿命の延長は社会的に喫緊の課題である。要支援の主な原因となる転倒/骨折を予防するためには筋力強化が重要である。現在のところ、筋力強化に資する代表的な分子はアナボリックステロイドであるアンドロゲンであるが、心血管イベントを中心に多様な副作用リスクを有し問題である。アンドロゲンはアンドロゲン受容体（AR）を介してその作用を発揮する。ARをはじめとする核内受容体は、これまでリガンドと結合することでDNA上の結合配列に結合し標的遺伝子の発現を制御すると考えられてきた。だが近年、これらの結合配列近傍には“パイオニア因子”と呼ばれる別の転写因子群が存在し、核内受容体の組織特異的な転写調節能を規定していることが明らかとなってきた。しかしながら、骨格筋におけるARのパイオニア因子の詳細は全く不明である。この因子は骨格筋のアンドロゲン応答能を規定していると予想される。そこで本研究では、新たなプロテオミクスの手法を導入することで、骨格筋細胞におけるARのパイオニア因子を同定・解析することを目的としている。本研究の成果はサルコペニアなどの筋力低下疾患に対する副作用の少ない治療法開発につながることが期待される。本年度の実験では、このプロテオミクスの実験材料とするための培養筋管細胞を用いたアンドロゲン応答系の構築を行った。マウス由来筋芽細胞C2C12細胞を用いてDHTに感度良く応答する培養細胞の樹立に成功した。次年度より、この細胞を用いたプロテオミクス実験を進めARのパイオニア因子の取得を行いたいと考えている。
ゲノムワイドCRISPRスクリーニング法を用いた糖尿病性腎症の新規創薬・病態解明

菅原明, 岩渕好治, 横山敦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 挑戦的研究(萌芽)

Institution: 東北大学

2021/07/09 - 2023/03/31

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我々は、当該年度の下記の成果を得た。１)D532の標的遺伝子の解析：我々は野生型マウス群、1型糖尿病性腎症モデルマウスであるiNOS-トランスジェニック（TG）マウス＋Vehicle群、iNOS-TGマウス＋D532群の各腎臓から抽出したRNAを用いて、RNA-Sequenceを施行した。その結果、Lpk、Fis1、Kcnb1、Dguok、Slc25a15といったChREBPの標的遺伝子に加えて、Txnipも野生型マウス群に比してiNOS-TGマウス群でその発現が著明に増加していた一方で、iNOS-TGマウス＋D532群では発現が顕著に減少していることが明らかとなった。また、GO enrichment analysisでも細胞内シグナル伝達経路やアポトーシス経路の有意な変動が観察された。以上の結果から、TxnipがD532の下流に存在することが確認された。現在、更なるパスウェイ解析を行うことにより、D532作用時の腎臓におけるTxnipの上流遺伝子を検索中である。２）CRISPR-Cas9システムによるChREBP KOマウスの作成：ChREBPのDNA結合ドメインであるヘリックス-ループ-ヘリックス構造（Exon 13～14内）を含むExon 12からExon 14を認識するcrRNAを作製し、マウス受精卵（B6N×B6N）に対してエレクトロポレーション法によりCas9 protein 100 ng/μL、100 ng/μL crRNAs、100 ng/μL tracrRNAを導入した。作製した受精卵は偽妊娠雌マウスの卵管に導入し、変異マウスは胎生19日目に出生した。得られたChREBP KOマウス腎臓でのChREBP欠損はWestern blotによって確認された。
VIKING法を用いた膵β細胞におけるChREBPと炎症シグナルのクロストークメカニズムの解明

Offer Organization: 徳島大学先端酵素学研究所

System: 共同研究

2022/07 - 2023/03
糖質応答転写因子ChREBPを標的とした糖尿病性腎症の病態解明・新規創薬

菅原明, 岩渕好治, 横山敦, 岡本好司

Offer Organization: 日本学術振興会

System: 科学研究費助成事業基盤研究(B)

Category: 基盤研究(B)

Institution: 東北大学

2020/04 - 2023/03

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我々は当該年度に以下の実験を遂行した。１）糖尿病性腎症（DN）の発症・増悪におけるChREBPの関与・作用機構の解明：A) CRISPR/Cas9システムを用いて作成したChREBPノックアウトマウスからRNAを抽出してRNAシークエンスに供する準備を進めている。B）東北大学医学部倫理委員会にて承認を得たことから、東北大学病院腎・高血圧・内分泌科の腎生検組織からのRNA抽出・RNAシークエンスに向けて、DNならびに非DN検体の準備を進めている。２）D532のDN改善効果の機序解明および実用化・臨床応用に向けた構造最適化：A）D532の一端を伸長して末端をビオチン化することにより作成したD532プローブを用いて、アビジン‐ビオチン反応を利用したアフィニティ精製・質量分析にてD532の標的因子の同定を進めた結果、ChREBP自身がD532の標的因子であることが明らかとなった。B）ChIPアッセイの結果、D532がChREBPのDNAへの結合を抑制することが認められた。本結果から、D532が高血糖依存性のChREBP転写活性をDNA結合レベルで抑制することが明らかとなった。C）D532はChREBPの核内移行には影響を及ぼさないことが明らかとなった。D）疎水性であるD532をPMB30Wにてミセル化することにより水溶化が出来ることが明らかとなった。本成果により、今後のD532を用いた非臨床試験・臨床試験に向けて大きく前進できるものと期待される。
VIKIG法を用いた膵β細胞におけるChREBPと炎症シグナルのクロストークメカニズムの解明

横山敦

Offer Organization: 徳島大学先端酵素学研究所

System: 国立大学法人徳島大学徳島大学先端酵素学研究所（共同研究）

2021/04 - 2022/03
Identification of a novel adipocyte-derived factor that elevates blood pressure using VIKING method

Sugawara Akira

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

Category: Grant-in-Aid for Challenging Research (Exploratory)

Institution: Tohoku University

2019/06 - 2021/03

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Hypertension is a frequently observed complication among obese patients with metabolic syndrome. In this study, we aim to identify the undetermined adipocyte-derived factor(s) that stimulate aldosterone synthase gene (CYP11B2) expression and aldosterone secretion that may induce obesity-related hypertension. We first differentiated mouse fibroblast 3T3-L1 cells into adipocytes, and collected their supernatants. The supernatants were incubated with human adrenocortical carcinoma H295R cells, and their CYP11B2 mRNA expression was measured by quantitative PCR with reverse transcription. The supernatants were then purified by anion-exchange chromatography and were further fractionated by LC-MS/MS. We then identified several candidate proteins and are investigating their function by shRNA.
VIKING法を用いた皮膚細胞でのビタミンD 受容体転写制御メカニズムの解析 Competitive

横山敦

Offer Organization: 国立大学法人徳島大学

System: 徳島大学先端酵素学研究所（共同研究）

2019/04 - 2020/03
The identification of undetermined adipocyte-derived factor(s) that stimulate aldosterone synthase gene (CYP11B2) expression

Sugawara Akira, YOKOYAMA atushi, KUDO masataka, DOI takayuki, ITO ryo, SHIMADA hiroki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

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

Institution: Tohoku University

2016/04 - 2019/03

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Obese patients are well known to be highly complicated with hypertension. Recently, “undetermined” adipocyte-derived factor(s) have been recognized as one of the causes of the obesity-related hypertension independent of angiotensin II. In the present study, we aim to identify the undetermined adipocyte-derived factor(s) that stimulate aldosterone synthase gene (CYP11B2) expression and aldosterone secretion that may induce hypertension. We first differentiated mouse fibroblast 3T3-L1 cells into adipocytes, and collected their supernatants. The supernatants were then incubated with human adrenocortical carcinoma H295R cells, and their ability to stimulate CYP11B2 mRNA expression was indicated. Thereafter, the supernatants were fractionated by ultrafiltration to obtain active fractions that stimulate CYP11B2 expression, and proteins included in the fractions were analyzed by LC-MS/MS. We finally obtained factor "X" which was demonstrated to stimulate CYP11B2 expression significantly.
Elucidation of the mechanism of regulon switching controlled by Ad4BP

BABA Takashi, Yokoyama Atsushi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

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

Institution: Kyushu University

2016/04 - 2019/03

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In this study, we identified three acetylation sites (K45, K392, and K435) of Ad4BP protein. Then, we tried to generate monoclonal antibodies recognizing each acetylated protein. We succeeded in generating anti-K392Ac-Ad4BP antibody, and are screening anti-K45Ac-Ad4BP and anti-K392Ac-Ad4BP antibodies. Spatio-temporal localization of acetylated Ad4BP in vivo will be determined by immunohistochemical staining with the antibodies. Moreover, we will perform ChIP-seq to identify genes regulated by acetylated Ad4BP to understand the mechanism of "regulon switching" in response to environmental stimuli.
Screening of drug target proteins for diabetic nephropathy by identification of ChREBP complex from renal mesangial cells Competitive

Yokoyama Atsushi, SHIMA hiroki, SUGAWARA akira, NORO erika

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

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

Institution: Tohoku University

2016/04 - 2019/03

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In this research projecct, we focused on ChREBP, a DNA-binding transcription factor which is believed to be involved in diabetic nephropathy pathogenesis. To understand ChREBP-mediated transcriptional regulation, we tried to identify ChREBP-containing protein complex using renal mesangial cells. In this attempt, we identified several coregulator candidates for ChREBP and, we also identified cross-talk mechanisms between ChREBP and inflammation signals. To developing drugs targeting these factors might be promising strategy for diabetic nephropathy and other metabolic syndromes.
Innovation of novel therapeutics against diabetic nephropathy targeting ChREBP

Sugawara Akira, SAWATUBASHI Shun, TAKEMOTO Tatsuya, YAMAMOTO Yasuhiko, TAKAGI Kiyoshi, Sato Horoshi, Yokoyama Atsushi, ITO Ryo, DOI Takayuki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

Category: Grant-in-Aid for Challenging Exploratory Research

Institution: Tohoku University

2016/04 - 2018/03

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1) Generation of ChREBP KO mice. We have succeeded in generating ChREBP KO mice (C57BL/6J) using CRISPR/Cas9 system. 2) Generation of high throughput screening (HTS) system using MES13 ChoRE-Luc cells. We have succeeded in generating HTS system using the cell line by obtaining Z score above 0.5. 3) HTS of Tohoku University chemical library: We obtained 13 hit chemicals among 5,861 compounds. Among them, we selected 1 compound (X) for the further investigation. 4) Administration of chemical compounds to Ins-iNOS-transgenic mice: We are now administrating the compound X to the mice.
糖尿病性腎症におけるグルコース依存性転写因子ChREBPの解析 Competitive

横山敦

Offer Organization: 国立大学法人徳島大学

System: 徳島大学先端酵素学研究所（共同利用）

2016/04 - 2017/03
Competitive

横山敦

Offer Organization: 公益財団法人山口内分泌疾患研究振興財団

System: 山口内分泌疾患研究振興財団助成金

2015/04 - 2016/03
Establishment of sex differences through sex-specific enhancer

MOROHASHI Ken-ichirou, SHIMA Yuichi, BABA Takashi, YOKOYAMA Atsushi, MATSUMOTO Takahiro

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Institution: Kyushu University

2010/04 - 2016/03

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The gonads, testis and ovary, acquire the sexes under genetic regulation, and then establish endocrine regulation by starting sex steroid production. Thereafter, genetic and endocrine regulation, through their synergistic interaction, result in exhibition of sex differences in the gonads and other many organs. In the present study, based on the hypothesis that the sex-dependent gene expression in the establishment of the sex differences would be regulated by sex-specific chromatin structure via variety of histone modification, we aimed to uncover the molecular bases for establishment of the sex differences. In particular, we focused on the function of Ad4BP essential for gonadal development and the chromatin structure. As the consequence, we succeeded to elucidate the molecular mechanisms for sex-dependent differentiation of Sertoli (nursing cells) and Leydig cells (steroid hormone producing cells), both of which are crucial for testicular functions.
Identification of novel PTMs Competitive

YOKOYAMA Atsushi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

Category: Grant-in-Aid for Challenging Exploratory Research

2012/04/01 - 2014/03/31

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In this project, we succeeded to identify at least one novel PTM. As a substrate of the novel PTM, we utilized histone proteins. To validate the existence of the novel PTM, we performed in vitro modification assays with radio-active compounds. Furthermore, we succeeded to generate the antibodies recognizing the PTM. These results are significant for future experiments for analyzing the novel PTM.
アルドステロン合成酵素の転写制御因子複合体の同定による新たな高血圧治療の分子標的の探索 Competitive

横山敦

Offer Organization: 科学技術振興機構

System: A-STEPフィージビリティスタディステージ探索タイプ

2013/04 - 2014/03
Analysis of nuclear lipidation in gene regulation

YOKOYAMA Atsushi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

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

Institution: The University of Tokyo

2010 - 2011

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This year we performed proteomic analysis of purified endogenous HN4 protein using the scheme established last year. First of all, we purified endogenous HNF4 protein by affinity purification, then samples were subjected to LC-MS/MS analysis. From this experiment, we identified 14 PTM sites in HNF4 protein such as phosphorylation, acetylation, methylation and ubiquitilation. This result was reported to the scientific journal as an original paper(Yokoyama et al., Biochem Biophys Res Commun, 2011, 410(4): 749-5). However, we could not identify the lipidation of HNF4 in this experiment. Furthermore, we adopted the novel method "click-it reaction" for the proteomic analysis of nuclear lipidation. In this method, labeled proteins were purified by avidin beads, and then subjected to the LC-MS/MS analysis. As a result, we identified various proteins including HNF4 and histone protein. We think this result implies that nuclear lipidation has more global role than we expected before, and now we are preparing the manuscript for the paper concerning this results.
TLX転写共役因子複合体の同定と解析による、神経幹細胞未分化維持機構の解明

横山敦

Offer Organization: 日本学術振興会

System: 科学研究費助成事業特別研究員奨励費

Category: 特別研究員奨励費

Institution: 東京大学

2007 - 2008

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ヒト網膜芽細胞腫由来細胞株Y79細胞を大量培養し、核抽出液を取得する実験系を確立し、オーファン核内受容体に結合する転写共役因子複合体としてヒストン脱メチル化酵素LSD1複合体を見出した。その後の解析により、LSD1はTLXに直接結合し、ヒストン脱メチル化活性によりTLXの転写抑制機能を担っている共役転写抑制因子であることが判明した。さらに、LSD1はヒストン脱アセチル化酵素であるHADc1/2をリクルートし、そのヒストン脱アセチル化活性を発揮させていることがわかった。また、TLXはLSD1複合体を標的遺伝子上にリクルートすることにより、標的遺伝子の一つであるPTEN遺伝子の発現を抑制し細胞増殖を正に制御していることが示唆されるデータを得ることが出来た。これらの結果は、原著論文として科学誌に掲載された。(Yokoyama et al,Mol Cell Biol,in press) さらに、LSD1転写共役因子複合体が各細胞株において異なった構成因子により存在するとの仮説のもと、様々な肺胞株を用いて生化学的な精製実験を行ったところ、マウス神経芽腫由来細胞株Neuro2a細胞の核抽出液から新規の相互作用因子の取得に成功し、数種類の新規LSD1複合体構成因子を同定することに成功することができた。なかでも、神経細胞特異的に発現する因子を数種得ることができたため、これらの因子について神経分化における役割について現在鋭意解析中である。

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Teaching Experience 13

検査医科学概論　東北大学大学院医学系研究科
自動化機器論　東北大学医学部保健学科検査技術科学専攻
一般検査学実習　東北大学医学部保健学科検査技術科学専攻
免疫化学実習　東北大学医学部保健学科検査技術科学専攻
生命科学B　東北大学
医学研究法II 生理学・薬理学研究技法　北海道大学大学院医学研究院
病態学関連英語　東北大学医学部保健学科検査技術科学専攻
分子生物学　東北大学医学部保健学科検査技術科学専攻
検査学基礎実習Ⅰ　東北大学医学部保健学科検査技術科学専攻
臨床分析生化学　東北大学医学部保健学科検査技術科学専攻
-　Tohoku University, School of Health Sciences, School of Medicine, Faculty of Medicine
-　Tohoku University, School of Health Sciences, School of Medicine, Faculty of Medicine
-　Tohoku University

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