Details of the Researcher

PHOTO

Hiroki Takahashi
Section
Graduate School of Medicine
Job title
Assistant Professor
Degree

  • PhD. (The University of Tokyo)

e-Rad No.
00909822

Research History 3

  • 2021/04 - Present
    Tohoku University　Graduate School of Medicine　Assistant professor

  • 2020/04 - 2021/03
    The University of Tokyo　Research Center for Advanced Science and Technology　Postdoctoral Fellow (JSPS PD)

  • 2019/04 - 2020/03
    The University of Tokyo　Graduate School of Medicine　Research Fellow (JSPS DC2)

Research Areas 4

  • Life sciences / Metabolism and endocrinology /

  • Life sciences / Physiology /

  • Life sciences / Clinical pharmacy /

  • Life sciences / Molecular biology /

Awards 8

  1. AOCO Rising Star Award

    2024/10　Asia Oceania Association for the Study of Obesity

  2. Tohoku Medical Society Scholarship Award A

    2024/01　Tohoku University School of Medicine

  3. Young Investigator Award

    2023/11　Japan Society of Cardiovascular Endocrinology and Metabolism

  4. Young Investigator Award

    2023/11　Japan Society for the Study of Obesity

  5. Adiposcience Symposium Young Investigator Award

    2023/01　Japan Society for the Study of Obesity

  6. Young Investigator Award

    2022/06　Japan Endocrine Society

  7. Medical Encouragement Award

    2022/01　Miyagi Medical Association

  8. Tohoku University Medical School Scholarship Award (Silver Medal)

    2022/01　Tohoku University School of Medicine

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Papers 6

  1. Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling Peer-reviewed

    Chenxu Yang, Makoto Arai, Eko Fuji Ariyanto, Ji Zhang, Debby Mirani Lubis, Ryo Ito, Shiyu Xie, Mio Nitta, Fuka Kawashima, Tomofumi Ishitsuka, Chaoran Yang, Tomohiro Suzuki, Tetsuro Komatsu, Hina Sagae, Hitomi Jin, Hiroki Takahashi, Eri Kobayashi, Yuchen Wei, Bohao Liu, Hyunmi Choi, Youichiro Wada, Toshiya Tanaka, Tsuyoshi Osawa, Hiroshi Kimura, Tatsuhiko Kodama, Hiroyuki Aburatani, Makoto Tachibana, Yoichi Shinkai, Takeshi Inagaki, Tomoyoshi Soga, Timothy F. Osborne, Takeshi Yoneshiro, Yoshihiro Matsumura, Juro Sakai

    Cell Reports　44　(8)　116060-116060　2025/08

    Publisher: Elsevier BV

    DOI： 10.1016/j.celrep.2025.116060 　

    ISSN： 2211-1247

  2. Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease Peer-reviewed

    Ryo Ito, Shiyu Xie, Myagmar Tumenjargal, Yuto Sugahara, Chaoran Yang, Hiroki Takahashi, Makoto Arai, Shin-Ichi Inoue, Aoi Uchida, Kenji Nakano, Hyunmi Choi, Ge Yang, Yanan Zhao, Rei Yamaguchi, Hitomi Jin, Hina Sagae, Youichiro Wada, Toshiya Tanaka, Hiroshi Kimura, Tatsuhiko Kodama, Hiroyuki Aburatani, Kazuhisa Takeda, Takeshi Inagaki, Timothy F. Osborne, Takeshi Yoneshiro, Yoshihiro Matsumura, Juro Sakai

    iScience　27　(4)　109398-109398　2024/04

    Publisher: Elsevier BV

    DOI： 10.1016/j.isci.2024.109398 　

    ISSN： 2589-0042

  3. Environmental factor reversibly determines cellular identity through opposing Integrators that unify epigenetic and transcriptional pathways Invited Peer-reviewed

    Hiroki Takahashi, Ryo Ito, Yoshihiro Matsumura, Juro Sakai

    BioEssays　46　(2)　2023/11/27

    Publisher: Wiley

    DOI： 10.1002/bies.202300084 　

    ISSN： 0265-9247

    eISSN： 1521-1878

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    Abstract Organisms must adapt to environmental stresses to ensure their survival and prosperity. Different types of stresses, including thermal, mechanical, and hypoxic stresses, can alter the cellular state that accompanies changes in gene expression but not the cellular identity determined by a chromatin state that remains stable throughout life. Some tissues, such as adipose tissue, demonstrate remarkable plasticity and adaptability in response to environmental cues, enabling reversible cellular identity changes; however, the mechanisms underlying these changes are not well understood. We hypothesized that positive and/or negative “Integrators” sense environmental cues and coordinate the epigenetic and transcriptional pathways required for changes in cellular identity. Adverse environmental factors such as pollution disrupt the coordinated control contributing to disease development. Further research based on this hypothesis will reveal how organisms adapt to fluctuating environmental conditions, such as temperature, extracellular matrix stiffness, oxygen, cytokines, and hormonal cues by changing their cellular identities.

  4. MYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis Peer-reviewed

    Hiroki Takahashi, Ge Yang, Takeshi Yoneshiro, Yohei Abe, Ryo Ito, Chaoran Yang, Junna Nakazono, Mayumi Okamoto-Katsuyama, Aoi Uchida, Makoto Arai, Hitomi Jin, Hyunmi Choi, Myagmar Tumenjargal, Shiyu Xie, Ji Zhang, Hina Sagae, Yanan Zhao, Rei Yamaguchi, Yu Nomura, Yuichi Shimizu, Kaito Yamada, Satoshi Yasuda, Hiroshi Kimura, Toshiya Tanaka, Youichiro Wada, Tatsuhiko Kodama, Hiroyuki Aburatani, Min-Sheng Zhu, Takeshi Inagaki, Timothy F. Osborne, Takeshi Kawamura, Yasushi Ishihama, Yoshihiro Matsumura, Juro Sakai

    Nature Communications　13　(1)　2022/09/29

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41467-022-33363-0 　

    eISSN： 2041-1723

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    Abstract Protein kinase A promotes beige adipogenesis downstream from β-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion results in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1β also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Pre-adipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators.

  5. Spatiotemporal dynamics of SETD5-containing NCoR–HDAC3 complex determines enhancer activation for adipogenesis Peer-reviewed

    Yoshihiro Matsumura, Ryo Ito, Ayumu Yajima, Rei Yamaguchi, Toshiya Tanaka, Takeshi Kawamura, Kenta Magoori, Yohei Abe, Aoi Uchida, Takeshi Yoneshiro, Hiroyuki Hirakawa, Ji Zhang, Makoto Arai, Chaoran Yang, Ge Yang, Hiroki Takahashi, Hitomi Fujihashi, Ryo Nakaki, Shogo Yamamoto, Satoshi Ota, Shuichi Tsutsumi, Shin-ichi Inoue, Hiroshi Kimura, Youichiro Wada, Tatsuhiko Kodama, Takeshi Inagaki, Timothy F. Osborne, Hiroyuki Aburatani, Koichi Node, Juro Sakai

    Nature Communications　12　(1)　2021/12/02

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41467-021-27321-5 　

    eISSN： 2041-1723

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    Abstract Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.

  6. Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch Peer-reviewed

    Yohei Abe, Yosuke Fujiwara, Hiroki Takahashi, Yoshihiro Matsumura, Tomonobu Sawada, Shuying Jiang, Ryo Nakaki, Aoi Uchida, Noriko Nagao, Makoto Naito, Shingo Kajimura, Hiroshi Kimura, Timothy F. Osborne, Hiroyuki Aburatani, Tatsuhiko Kodama, Takeshi Inagaki, Juro Sakai

    Nature Communications　9　(1)　2018/04/19

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41467-018-03868-8 　

    eISSN： 2041-1723

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    Abstract In acute cold stress in mammals, JMJD1A, a histone H3 lysine 9 (H3K9) demethylase, upregulates thermogenic gene expressions through β-adrenergic signaling in brown adipose tissue (BAT). Aside BAT-driven thermogenesis, mammals have another mechanism to cope with long-term cold stress by inducing the browning of the subcutaneous white adipose tissue (scWAT). Here, we show that this occurs through a two-step process that requires both β-adrenergic-dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A. The histone demethylation-independent acute Ucp1 induction in BAT and demethylation-dependent chronic Ucp1 expression in beige scWAT provides complementary molecular mechanisms to ensure an ordered transition between acute and chronic adaptation to cold stress. JMJD1A mediates two major signaling pathways, namely, β-adrenergic receptor and peroxisome proliferator-activated receptor-γ (PPARγ) activation, via PRDM16-PPARγ-P-JMJD1A complex for beige adipogenesis. S265 phosphorylation of JMJD1A, and the following demethylation of H3K9me2 might prove to be a novel molecular target for the treatment of metabolic disorders, via promoting beige adipogenesis.

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Misc. 4

  1. Advances in Epigenomic Research on Diabetes

    DIABETES　16　(2)　14-20　2024/12

  2. 交感神経-エピゲノム軸による脂肪細胞の環境適応機構

    伊藤亮, 高橋宙大, 荒井誠, 稲垣毅, 米代武司, 松村欣宏, 酒井寿郎

    実験医学　41　(20)　29-37　2023/12

  3. Mechanisms of Adipocyte Fate Determination Through Epigenetic Changes in Response to Environmental Fluctuations.

    Bio Industry　40　(5)　45-56　2023/05

  4. Multi-omics in lifestyle-related diseases

    実験医学　41　(15)　2023

Research Projects 3

  1. Elucidation of central epigenomic mechanisms regulating energy balance

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Early-Career Scientists

    Institution: Tohoku University

    2025/04 - 2030/03

  2. Elucidation of the mechanism of beiging through identification of phosphatase of histone demethylase JMJD1A

    Takahashi Hiroki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Research Activity Start-up

    Institution: Tohoku University

    2021/08 - 2023/03

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    Beige adipocytes are thermogenic adipocytes induced in white fat by chronic cold exposure and are attracting attention as a novel strategy for the treatment and prevention of obesity. In this study, we identified MYPT1-PP1β as a phosphatase of JMJD1A, a histone demethylase crucial for beiging, and found that their activity is inhibited via PKA-dependent phosphorylation, increasing phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion results in JMJD1A-mediated H3K9 demethylation and activation of Ucp1 gene. In addition, MYPT1-PP1β suppresses beiging by dephosphorylating myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ. Pre-adipocyte specific Mypt1 deficient mice exhibit enhanced beiging, improved die-induced obesity, and glucose metabolism. Thus, we have uncovered regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of transcriptional co-activators.

  3. 脱リン酸化阻害によるＪＭＪＤ１Ａリン酸化維持によりベージュ化が誘導されるかの解明

    高橋 宙大

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特別研究員奨励費

    Institution: 東京大学

    2019/04 - 2021/03

    More details Close

    ベージュ脂肪細胞は、慢性寒冷下、皮下白色脂肪組織（scWAT）中に誘導される熱産生脂肪細胞で、熱産生にエネルギーを消費する事から、肥満が成因基盤となる生活習慣病の治療標的として注目される。我々は、先行研究で、ヒストン脱メチル化酵素JMJD1Aが、265番目のセリンのリン酸化依存的に、エピゲノム記憶を書き換える事で、ベージュ化を誘導する事を見出していた。この結果から、JMJD1Aの脱リン酸化酵素の阻害が、リン酸化修飾を安定化させる事で、エピゲノム変化を熱産生遺伝子座で制御し、ベージュ化を誘導する可能性が示唆された。そこで本研究では、JMJD1Aの脱リン酸化酵素を同定し、此れの阻害により、ベージュ化が誘導されるか解明した。質量分析解析より、リン酸化JMJD1Aの脱リン酸化酵素の候補タンパク質として、ミオシンホスファターゼの調節サブユニットMYPT1と触媒サブユニットPP1βを同定し、共免疫沈降法により、相互作用の確認に成功した。更に、これらのリン酸化JMJD1A脱リン酸化酵素候補遺伝子をRNAi干渉によりノックダウンすると、JMJD1Aのリン酸化レベルが増加し、熱産生遺伝子座のH3K9me2レベルが減少し、且つ熱産生遺伝子が顕著に誘導される事を明らかにした。 以上、JMJD1Aの脱リン酸化酵素として、MYPT1-PP1β脱リン酸化酵素複合体を同定し、これの阻害がベージュ化誘導を促進し、その分子機構がエピゲノムの安定化を介する遺伝子転 調節機構に基づく可能性を見いだした。