Research Achievements - Original paper -

Pre-fertilization-origin preservation of brown fat-mediated energy expenditure in humans

Takeshi Yoneshiro, Mami Matsushita, Sayuri Fuse-Hamaoka, Miyuki Kuroiwa, Yuko Kurosawa, Yosuke Yamada, Makoto Arai, Yuchen Wei, Makoto Iida, Kenichi Kuma, Toshimitsu Kameya, Tomoya Harada, Yoshihiro Matsumura, Tsuyoshi Osawa, Yoshiko Aoki, Hisashi Nakamura, Takafumi Hamaoka, Juro Sakai, Masayuki Saito

Nature Metabolism     2025.02  [Refereed]

Research paper (journal)   Domestic Co-author

β-Adrenergic Signal and Epigenomic Regulatory Process for Adaptive Thermogenesis

Yoshihiro Matsumura, Timothy F Osborne, Ryo Ito, Hiroki Takahashi, Juro Sakai

Advances in Experimental Medicine and Biology ( Springer )  1461   213 - 227   2024.11

Research paper (journal)   International Co-author

DOI PubMed

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

Ito R, Xie S, Tumenjargal M, Sugahara Y, Yang C, Takahashi H, Arai M, Inoue SI, Uchida A, Nakano K, Choi H, Yang G, Zhao Y, Yamaguchi R, Jin H, Sagae H, Wada Y, Tanaka T, Kimura H, Kodama T, Aburatani H, Takeda K, Inagaki T, Osborne TF, Yoneshiro T, Matsumura Y, Sakai J.

iScience ( iScience )  27 ( 4 ) 109398 - 109398   2024.04  [Refereed]

Research paper (journal)  

Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

DOI PubMed

Environmental factor reversibly determines cellular identity through opposing Integrators that unify epigenetic and transcriptional pathways.

Hiroki Takahashi, Ryo Ito, Yoshihiro Matsumura, Juro Sakai

BioEssays : news and reviews in molecular, cellular and developmental biology ( BioEssays )  46 ( 2 ) e2300084   2023.11  [Refereed]

Research paper (journal)   Domestic Co-author

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.

DOI PubMed

Hypoxia activates SREBP2 through Golgi disassembly in bone marrow-derived monocytes for enhanced tumor growth.

Ryuichi Nakahara, Sho Aki, Maki Sugaya, Haruka Hirose, Miki Kato, Keisuke Maeda, Daichi M Sakamoto, Yasuhiro Kojima, Miyuki Nishida, Ritsuko Ando, Masashi Muramatsu, Melvin Pan, Rika Tsuchida, Yoshihiro Matsumura, Hideyuki Yanai, Hiroshi Takano, Ryoji Yao, Shinsuke Sando, Masabumi Shibuya, Juro Sakai, Tatsuhiko Kodama, Hiroyasu Kidoya, Teppei Shimamura, Tsuyoshi Osawa

The EMBO journal ( EMBO Journal )  42 ( 22 ) e114032   2023.10  [Refereed]

Research paper (journal)   Domestic Co-author

Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner. Notably, hypoxia-induced SREBP2 activation was only observed in an immature lineage of bone marrow-derived cells. Single-cell RNA-seq analysis revealed that SREBP2-mediated cholesterol biosynthesis was upregulated in HSCs and monocytes but not in macrophages in the hypoxic bone marrow niche. Moreover, inhibition of cholesterol biosynthesis impaired tumor growth through suppression of pro-tumorigenic immunity and angiogenesis. Thus, our findings indicate that Golgi-ER fusion regulates SREBP2-mediated metabolic alteration in lineage-specific BMDCs under hypoxia for tumor progression.

DOI PubMed

Epitranscriptomics in metabolic disease.

Yoshihiro Matsumura, Fan-Yan Wei, Juro Sakai

Nature Metabolism ( Nature Metabolism )  5 ( 3 ) 370 - 384   2023.03  [Refereed]

Research paper (journal)   Domestic Co-author

While epigenetic modifications of DNA and histones play main roles in gene transcription regulation, recently discovered post-transcriptional RNA modifications, known as epitranscriptomic modifications, have been found to have a profound impact on gene expression by regulating RNA stability, localization and decoding efficiency. Importantly, genetic variations or environmental perturbations of epitranscriptome modifiers (that is, writers, erasers and readers) are associated with obesity and metabolic diseases, such as type 2 diabetes. The epitranscriptome is closely coupled to epigenetic signalling, adding complexity to our understanding of gene expression in both health and disease. Moreover, the epitranscriptome in the parental generation can affect organismal phenotypes in the next generation. In this Review, we discuss the relationship between epitranscriptomic modifications and metabolic diseases, their relationship with the epigenome and possible therapeutic strategies.

DOI PubMed

Spatiotemporal dynamics of SETD5-containing NCoR–HDAC3 complex determines enhancer activation for adipogenesis

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 ( Nature Communications )  12 ( 1 )   2021.12  [Refereed]

Research paper (journal)   International Co-author

DOI PubMed

Ubiquitination-dependent and -independent repression of target genes by SETDB1 reveal a context-dependent role for its methyltransferase activity during adipogenesis

Ji Zhang, Yoshihiro Matsumura, Yuka Kano, Ayano Yoshida, Takeshi Kawamura, Hiroyuki Hirakawa, Takeshi Inagaki, Toshiya Tanaka, Hiroshi Kimura, Shigeru Yanagi, Kiyoko Fukami, Takefumi Doi, Timothy F Osborne, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai

Genes to Cells ( Genes to Cells )  26 ( 7 ) 513 - 529   2021.07  [Refereed]

Research paper (journal)   International Co-author

The lysine methyltransferase SETDB1, an enzyme responsible for methylation of histone H3 at lysine 9, plays a key role in H3K9 tri-methylation-dependent silencing of endogenous retroviruses and developmental genes. Recent studies have shown that ubiquitination of human SETDB1 complements its catalytic activity and the silencing of endogenous retroviruses in human embryonic stem cells. However, it is not known whether SETDB1 ubiquitination is essential for its other major role in epigenetic silencing of developmental gene programs. We previously showed that SETDB1 contributes to the formation of H3K4/H3K9me3 bivalent chromatin domains that keep adipogenic Cebpa and Pparg genes in a poised state for activation and restricts the differentiation potential of pre-adipocytes. Here, we show that ubiquitin-resistant K885A mutant of SETDB1 represses adipogenic genes and inhibits pre-adipocyte differentiation similar to wild-type SETDB1. We show this was due to a compensation mechanism for H3K9me3 chromatin modifications on the Cebpa locus by other H3K9 methyltransferases Suv39H1 and Suv39H2. In contrast, the K885A mutant did not repress other SETDB1 target genes such as Tril and Gas6 suggesting SETDB1 represses its target genes by two mechanisms; one that requires its ubiquitination and another that still requires SETDB1 but not its enzyme activity.

DOI PubMed

Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2.

Osawa T, Shimamura T, Saito K, Hasegawa Y, Ishii N, Nishida M, Ando R, Kondo A, Anwar M, Tsuchida R, Hino S, Sakamoto A, Igarashi K, Saitoh K, Kato K, Endo K, Yamano S, Kanki Y, Matsumura Y, Minami T, Tanaka T, Anai M, Wada Y, Wanibuchi H, Hayashi M, Hamada A, Yoshida M, Yachida S, Nakao M, Sakai J, Aburatani H, Shibuya M, Hanada K, Miyano S, Soga T, Kodama T

Cell Reports   29 ( 1 ) 89 - 103.e7   2019.10  [Refereed]

Research paper (journal)   Domestic Co-author

Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis. PEtn accumulation correlated with tumor growth under nutrient starvation. PCYT2 suppression was partially mediated by downregulation of the transcription factor ELF3. Furthermore, PCYT2 overexpression reduced PEtn levels and tumor growth. In addition, PEtn accumulation and PCYT2 downregulation in human breast tumors correlated with poor prognosis. Thus, we show that glutamine deprivation leads to tumor progression by regulating PE biosynthesis via the ELF3-PCYT2 axis. Furthermore, manipulating glutamine-responsive genes could be a therapeutic approach to limit cancer progression.

DOI PubMed

Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition.

Nagai N, Ohguchi H, Nakaki R, Matsumura Y, Kanki Y, Sakai J, Aburatani H, Minami T

PLoS Genetics   14 ( 11 ) e1007826   2018.11  [Refereed]

Research paper (journal)   Domestic Co-author

DOI PubMed

The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages

Rumi Hachiya, Takuya Shiihashi, Ibuki Shirakawa, Yorihiro Iwasaki, Yoshihiro Matsumura, Yumiko Oishi, Yukiteru Nakayama, Yoshihiro Miyamoto, Ichiro Manabe, Kozue Ochi, Miyako Tanaka, Nobuhito Goda, Juro Sakai, Takayoshi Suganami, Yoshihiro Ogawa

Scientific Reports   6   28845   2016.06  [Refereed]

Research paper (journal)   Domestic Co-author

DOI PubMed

H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation

Yoshihiro Matsumura, Ryo Nakaki, Takeshi Inagaki, Ayano Yoshida, Yuka Kano, Hiroshi Kimura, Toshiya Tanaka, Shuichi Tsutsumi, Mitsuyoshi Nakao, Takefumi Doi, Kiyoko Fukami, Timothy F Osborne, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai

Molecular Cell   60 ( 4 ) 584 - 596   2015.11  [Refereed]

Research paper (journal)   International Co-author

DOI PubMed

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Sana Raza-Iqbal, Toshiya Tanaka, Motonobu Anai, Takeshi Inagaki, Yoshihiro Matsumura, Kaori Ikeda, Akashi Taguchi, Frank J Gonzalez, Juro Sakai, Tatsuhiko Kodama

Journal of Atherosclerosis and Thrombosis     2015.08  [Refereed]

Research paper (journal)   International Co-author

DOI

JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis

Yohei Abe, Royhan Rozqie, Yoshihiro Matsumura, Takeshi Kawamura, Ryo Nakaki, Yuya Tsurutani, Kyoko Tanimura-Inagaki, Akira Shiono, Kenta Magoori, Kanako Nakamura, Shotaro Ogi, Shingo Kajimura, Hiroshi Kimura, Toshiya Tanaka, Kiyoko Fukami, Timothy F Osborne, Tatsuhiko Kodama, Hiroyuki Aburatani, Takeshi Inagaki, Juro Sakai

Nature Communications     2015.05  [Refereed]

Research paper (journal)   International Co-author

DOI

The FBXL10/KDM2B scaffolding protein associates with novel polycomb repressive complex-1 to regulate adipogenesis

Takeshi Inagaki, Satoshi Iwasaki, Yoshihiro Matsumura, Takeshi Kawamura, Toshiya Tanaka, Yohei Abe, Ayumu Yamasaki, Yuya Tsurutani, Ayano Yoshida, Yoko Chikaoka, Kanako Nakamura, Kenta Magoori, Ryo Nakaki, Timothy F Osborne, Kiyoko Fukami, Hiroyuki Aburatani, Tatsuhiko Kodama, Juro Sakai

Journal of Biological Chemistry     2015.02  [Refereed]

Research paper (journal)   International Co-author

DOI

Endoplasmic reticulum protein quality control is determined by cooperative interactions between Hsp/c70 protein and the CHIP E3 ligase

Yoshihiro Matsumura, Juro Sakai, William R Skach

Journal of Biological Chemistry   288 ( 43 ) 31069 - 31079   2013.10  [Refereed]

Research paper (journal)   International Co-author

DOI

Role of Hsc70 binding cycle in CFTR folding and endoplasmic reticulum-associated degradation

Yoshihiro Matsumura, Larry L David, William R Skach

Molecular Biology of the Cell   22 ( 16 ) 2797 - 2809   2011.08  [Refereed]

Research paper (journal)   International Co-author

DOI

Stepwise insertion and inversion of a type II signal anchor sequence in the ribosome-Sec61 translocon complex

Prasanna K Devaraneni, Brian Conti, Yoshihiro Matsumura, Zhongying Yang, Arthur E Johnson, William R Skach

Cell   146 ( 1 ) 134 - 147   2011.07  [Refereed]

Research paper (journal)   Single author

DOI

In vitro methods for CFTR biogenesis

Yoshihiro Matsumura, LeeAnn Rooney, William R Skach

Methods in Molecular Biology   741   233 - 253   2011.04

Research paper (journal)   Single author

DOI

Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis

Darren M Hutt, David Herman, Ana P C Rodrigues, Sabrina Noel, Joseph M Pilewski, Jeanne Matteson, Ben Hoch, Wendy Kellner, Jeffery W Kelly, Andre Schmidt, Philip J Thomas, Yoshihiro Matsumura, William R Skach, Martina Gentzsch, John R Riordan, Eric J Sorscher, Tsukasa Okiyoneda, John R Yates 3rd, Gergely L Lukacs, Raymond A Frizzell, Gerard Manning, Joel M Gottesfeld, William E Balch

Nature Chemical Biology   6 ( 1 ) 25 - 33   2010.01  [Refereed]

Research paper (journal)   International Co-author

DOI