栄養環境によるヒストンメチル化制御機構の解明

2014 Fiscal Year Annual Research Report

• Project Area: Crosstalk of transcriptional control and energy pathways by hub metabolites
• Project/Area Number: 26116708
• Research Institution: The University of Tokyo
• Principal Investigator: 酒井 寿郎 東京大学, 先端科学技術研究センター, 教授 (80323020)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: エピゲノム / メタボリックシンドローム / ヒストン脱メチル化酵素 / 脂肪細胞分化

Outline of Annual Research Achievements

脂肪細胞分化過程におけるメタボロミクス解析から、グルコース、インスリンなどによる分化刺激によってTCAサイクルで産生されるαケトグルタル酸（αKG）が3倍程度上昇するのを見出した。さらに、発現アレイ解析からイソクエン酸脱水化酵素 IDH3が数倍上昇するのを見出した。αKGはJMJDヒストン脱メチル化酵素の補酵素として脱メチル化を活性化させるが、実際、解糖系遺伝子の多くの遺伝子上のヒストンのメチル化（H3K9ジメチル）が減少し、転写が活性化されこれらの遺伝子発現は顕著に上昇した。実際に細胞応答としては細胞外酸性化速度、脂肪細胞の脂肪蓄積が上昇した。
さらに、H3K9ジメチルをはずすヒストン脱メチル化酵素を系統的にRNA干渉法によってノックダウンしたところ、白色脂肪細胞のモデル細胞である3T3-L1脂肪細胞で解糖系遺伝子の発現をエピジェネティックに制御するJMJDヒストン脱メチル化酵素を同定した。
αKGは解糖系が亢進することでTCAサイクルでの産生が上昇する。産生されたαKGはJMJDヒストン脱メチル化酵素を補酵素として活性化し、さらに解糖系遺伝子発現を上昇させ、結果として解糖系を亢進させ、脂肪蓄積を増加させることから、この系はポジティブフィードバックループをつくり、高グルコース高インスリン血症を誘導する過栄養、肥満の状況を栄養学的に悪化させるサイクルにも関与しうることが判明した。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

研究計画に挙げていた責任となるヒストン脱メチル化酵素の同定も進み、おおむね順調に進んでいる。

Strategy for Future Research Activity

JMJDヒストン脱メチル化酵素とイソクエン酸脱水素酵素IDH3に着目し、αケトグルタル酸の量によって制御される脂肪細胞におけるエピゲノムと代謝の関連についてさらに解析を進める。

Research Products

• [Journal Article] The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival (2016)
  • Author(s): Ohguchi H, Hideshima T, Bhasin MK, Gorgun GT, Santo L, Cea M, Mimura N, Suzuki R, Tai Y-T, Carrasco RD, Raje N, Richardson PG, Harigae H, Sanda T, Sakai J, Anderson KC
  • Journal Title: Nature Communications Volume: 7 Pages: 10258
  • DOI: 10.1038/ncomms10258
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis (2015)
  • Author(s): Abe Y, Rozqie R, Matsumura Y, Kawamura T, Nakaki R, Tsurutani Y, Tanimura-Inagaki K, Shiono A, Magoori K, Nakamura K, Ogi S, Kajimura S, Kimura H, Tanaka T, Fukami K, Osborne TF, Kodama T, Aburatani H, Inagaki T, Sakai J.
  • Journal Title: Nature Communications Volume: 6 Pages: 7052
  • DOI: 10.1038/ncomms8052
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver. (2015)
  • Author(s): Raza-Iqbal S, Tanaka T, Anai M, Inagaki T, Matsumura Y, Ikeda K, Taguchi A, Gonzalez FJ, Sakai J, Kodama T.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 22 Pages: 754-772
  • DOI: 10.5551/jat.28720
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Analysis of the subcellular localization of the human histone methyltransferase SETDB1 (2015)
  • Author(s): Tachibana K, Gotoh E, Kawamata N, Ishimoto K, Uchihara Y, Iwanari H, Sugiyama A, Kawamura T, Mochizuki Y, Tanaka T, Sakai J, Hamakubo T, Kodama T, Doi T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 465 Pages: 725-731
  • DOI: 10.1016/j.bbrc.2015.08.065
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation (2015)
  • Author(s): Matsumura Y, Nakaki R, Inagaki T, Yoshida A, Kano Y, Kimura H, Tanaka T, Tsutsumi S, Nakao M, Doi T, Fukami K, Osborne TF, Kodama T, Aburatani H, Sakai J
  • Journal Title: Molecular Cell Volume: 60 Pages: 584-596
  • DOI: 10.1016/j.molcel.2015.10.025
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The FBXL10/KDM2B Scaffolding Protein Associates with Novel Polycomb Repressive Complex-1 to Regulate Adipogenesis. (2015)
  • Author(s): Inagaki T, Iwasaki S, Matsumura Y, Kawamura T, Tanaka T, Abe Y, Yamasaki A, Tsurutani Y, Yoshida A, Chikaoka Y, Nakamura K, Magoori K, Nakaki R, Osborne TF, Fukami K, Aburatani H, Kodama T, Sakai J
  • Journal Title: Journal of Biological Chemistry Volume: 290 Pages: 4163-4177
  • DOI: 10.1074/jbc.M114.626929
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] PPARβ/δactivation of CD300a controls intestinal immunity. (2014)
  • Author(s): Tanaka T, Tahara-Hanaoka S, Mabekura T, Ikeda K, Jiang S, Tsutsumi S, Inagaki T, Magoori T, Higurashi H, Takahashi H, Tachibana K, Tsurutani Y, Raza S, Anai M , Minami T, Wada Y, Yokote K, Doi T, Hamakubo T, Auwerx J, Gonzalez J, Nakajima A, Aburatani H, Naito H, Shibuya A, Kodama T, Sakai J
  • Journal Title: Scientific Reports Volume: 4 Pages: 5412
  • DOI: 10.1038/srep05412
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Direct Evidence for Pitavastatin Induced Chromatin Structure Change in the KLF4 Gene in Endothelial Cells. (2014)
  • Author(s): Maejima T, Tanaka T, Minami T, Hamakubo T, Ihara S, Sakai J, Nozaki N, Aburatani H, Ruan X, Tanabe H, Ruan Y, Endo A, Kodama T, Wada Y
  • Journal Title: PLoS One Volume: 9 Pages: e96005
  • DOI: 10.1371/journal.pone.0096005
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipogenesis. (2016)
  • Author(s): 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, and Juro Sakai
  • Organizer: The Keystone Symposia -Chromatin and Epigenetics
  • Place of Presentation: Whistler, Canada
  • Year and Date: 2016-03-01
  • Int'l Joint Research
• [Presentation] Metabolic regulation of Adipocyte differentiation by isocitrate dehydrogenease and Jmjc histone (2015)
  • Author(s): 酒井寿郎, Eko F.Ariyant, 曽我朋義, 稲垣毅, 松村欣宏
  • Organizer: 第38回日本分子生物学会年会・第88回生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-03
  • Invited
• [Presentation] 細胞系譜特異的DNAメチル化により形成されるH3K4/H3K9me3クロマチンドメインは脂肪細胞分化を停止させる (2015)
  • Author(s): 松村欣宏, 吉田文乃, 仲木竜, 鹿野優佳, 稲垣毅, 油谷浩幸, 酒井寿郎
  • Organizer: 第38回日本分子生物学会年会・第88回生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-03
  • Invited
• [Presentation] SETDY Regulates C/EBP alpha Transcription during Adipogenesis (2015)
  • Author(s): 馬郡健太, 山﨑あゆむ, 大木翔太郎, 松村欣宏, 稲垣毅, 酒井寿郎
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-03
• [Presentation] Metabolic Regulation of Histone Demethylation and Glycolysis Gene Expression by Isocitrate Dehydrogenase 3 during Adipogenesis. (2015)
  • Author(s): Eko Fuji Ariyanto, Yoshihiro Matsumura, Tomoyoshi Soga, Takeshi Inagaki and Juro Sakai
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-03
• [Presentation] ヒストンメチル化酵素SETDB1のユビキチン化修飾 (2015)
  • Author(s): 鹿野優佳, 松村欣宏, 吉田文乃, 柳茂, 稲垣毅, 酒井寿郎
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-03
• [Presentation] Functional Analysis of the Transcriptional Regulation by Enhancers of the Thermogenesis Related Genes (2015)
  • Author(s): 小山一貴, 阿部陽平, 松村欣宏, 稲垣毅, 酒井寿郎
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-03
• [Presentation] JMJD1A is a Mediator of Long-Range Genomic Interactions to Regulate Metabolic Gene Expression (2015)
  • Author(s): Takeshi Inagaki, Yohei Abe, Royhan Rozqie, Yoshihiro Matsumura, Takeshi Kawamura, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai
  • Organizer: Keystone Symposia Conference;Diabetes
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2015-10-26
  • Int'l Joint Research
• [Presentation] Regulation of Higher-order Chromatin Structure during Thermogenesis in Brown Adipocytes (2015)
  • Author(s): Takeshi Inagaki, Yohei Abe, Royhan Rozqie, Yoshihiro Matsumura, Shingo Kajimura, Juro Sakai
  • Organizer: The 46th NIPS International Symposium
  • Place of Presentation: Nagoya
  • Year and Date: 2015-10-03
  • Int'l Joint Research / Invited
• [Presentation] PKA dependent phospho-switch on JMJD1A regulates higher-order chromatin dynamics via SWI/SNF and PPARγ association for thermogenesis. (2015)
  • Author(s): Yohei Abe, Royhan Rozqie, Yoshihiro Matsumura, Takeshi Kawamura, Ryo Nakaki, Shotaro Ogi, Toshiya Tanaka, Tatsuhiko Kodama, Hiroyuki Aburatani, Takeshi Inagaki, Juro Sakai
  • Organizer: EMBO Conference on Nuclear Receptors
  • Place of Presentation: Ajaccio, Corsica, France
  • Year and Date: 2015-09-24 – 2015-09-28
  • Int'l Joint Research
• [Presentation] JMJD1A Regulates Metabolic Gene Expression by Mediating Long-Range Genomic Interactions in Response to β-Adrenergic Stimulation under Cold Environment (2015)
  • Author(s): Inagaki, T., Abe, Y., Rozqie, R., Matsumura, Y., Kawamura, T., Nakaki, R., Kodama, T., Aburatani, H., Sakai, J.
  • Organizer: THE 40th NAITO CONFERENCE ON Epigenetics-From Histone Code to Therapeutic Strategy
  • Place of Presentation: Sapporo
  • Year and Date: 2015-09-17
• [Presentation] Lineage-specific gene-body DNA methylation and non-canonical H3K4/H3K9me3 bivalent chromatin domains maintain adipocyte lineage (2015)
  • Author(s): Yoshihiro Matsumura, Ayano Yoshida, Ryo Nakaki, Kenichi Wakabayashi, Takeshi Inagaki, Kiyoko Fukami, Hiroyuki Aburatani, Juro Sakai
  • Organizer: THE 40th NAITO CONFERENCE ON Epigenetics-From Histone Code to Therapeutic Strategy
  • Place of Presentation: Sapporo
  • Year and Date: 2015-09-15 – 2015-09-18
• [Presentation] β-Adrenergic induced phosphorylation of JMJD1A drives energy expenditure via SWI/SNF chromatin remodeler in Brown Adipocytes (2015)
  • Author(s): Sakai, J.
  • Organizer: The 47th Annual Scientific Meeting of the Japan Atherosclerosis Society
  • Place of Presentation: Sendai
  • Year and Date: 2015-07-10
  • Invited
• [Presentation] アディポバイオロジーを制御するヒストン脱メチル化酵素JMJD1Aの修飾シグナル (2015)
  • Author(s): 稲垣毅, 阿部陽平, Rozqie Royhan, 松村欣宏, 梶村真吾, 児玉龍彦, 油谷浩幸, 酒井寿郎
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] A Role of Isocitrate Dehydrogenase 3 in Regulation of Epigenome and Transcription during Adipogenesis (2015)
  • Author(s): Juro Sakai, Yoshihiro Matsumura, Ariyanto Fuji Eko, Takeshi Inagaki
  • Organizer: 12th Asian Congress of Nutrirtion
  • Place of Presentation: Yokohama
  • Year and Date: 2015-05-16
  • Int'l Joint Research / Invited
• [Presentation] 核内受容体PPARγとシグナル感知脱メチル化酵素によるエネルギー代謝制御機構 (2015)
  • Author(s): 酒井寿郎
  • Organizer: 第88回内分泌学会総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-25
  • Invited
• [Presentation] 脂肪細胞における新規エピゲノム制御機構 (2015)
  • Author(s): 稲垣毅, 阿部陽平, Rozqie Royhan, 松村欣宏, 川村猛, 仲木竜, 鶴谷悠也, 谷村恭子, 田中十志也, 児玉龍彦, 油谷浩幸, 酒井寿郎
  • Organizer: 第52回日本臨床分子医学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2015-04-11
  • Invited
• [Presentation] Lineage-specific gene-body DNA methylation recruits SETDB1 to form non-canonical bivalent chromatin domains that inhibit Cebpa and Pparg expressions and adipogenesis. (2015)
  • Author(s): Yoshihiro Matsumura, Ayano Yoshida, Ryo Nakaki, Ken-ichi Wakabayashi, Takeshi Inagaki, Kiyoko Fukami, Hiroyuki Aburatani, Juro Sakai
  • Organizer: DEUEL Conference on Lipids
  • Place of Presentation: Monterey, CA, USA
  • Year and Date: 2015-03-04
  • Int'l Joint Research
• [Presentation] PKA dependent phospho-switch on JMJD1A regulates higher-order chromatin dynamics via SWI/SNF association for thermogenesis. (2015)
  • Author(s): Yohei Abe, Royhan Rozqie, Yoshihiro Matsumura, Takeshi Kawamura, Ryo Nakaki, Yuya Tsurutani, Kyoko Tanimura-Inagaki, Akira Shiono, Kenta Magoori, Kanako Nakamura, Shingo Kajimura, Hiroshi Kimura, Toshiya Tanaka, Kiyoko Fukami, Timothy F. Osborne, Tatsuhiko Kodama, Hiroyuki Aburatani, Takeshi Inagaki, Juro Sakai
  • Organizer: DEUEL Conference on Lipids
  • Place of Presentation: Monterey, CA, USA
  • Year and Date: 2015-03-04
  • Int'l Joint Research
• [Presentation] FBXL10/KDM2B Regulates 3T3-L1 Adipogenesis via PRC1-dependent Transcriptional Repression. (2015)
  • Author(s): Takeshi Inagaki, Satoshi Iwasaki, Yoshihiro Matsumura, Yohei Abe, Timothy F. Osborne, Hiroyuki Aburatani, and Juro Sakai
  • Organizer: DEUEL Conference on lipids
  • Place of Presentation: Monterey, CA, USA
  • Year and Date: 2015-03-04
  • Int'l Joint Research
• [Presentation] PKA-dependent Association of Histone Demethylase JMJD1A with SWI/SNF and PPARγ Alters Chromatin Dynamics and Thermogenesis in Brown Adipocytes (2014)
  • Author(s): Juro Sakai
  • Organizer: The 37th Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Pacifico Yokohama, Yokohama
  • Year and Date: 2014-11-26
  • Invited
• [Presentation] Role of Isocitrate Dehydrogenase 3 in Regulation of Epigenome and Transcription during Adipogenesis (2014)
  • Author(s): Ariyanto, E.F., Matsumura, Y., Soga, T., Inagaki, T., Sakai, J.
  • Organizer: The 37th Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Pacifico Yokohama, Yokohama
  • Year and Date: 2014-11-26
• [Presentation] SETDB1は新規のクロマチンドメインを形成することでCebpαの転写と脂肪細胞分化を制御する (2014)
  • Author(s): 松村欣宏, 吉田文乃, 仲木竜, 鹿野優佳, 若林賢一, 稲垣毅, 深見希代子, 油谷浩幸, 酒井寿郎
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜, 横浜市
  • Year and Date: 2014-11-26
• [Presentation] ヒストンメチル化酵素SETDB1のユビキチン化修飾 (2014)
  • Author(s): 鹿野優佳, 松村欣宏, 吉田文乃, 稲垣毅, 酒井寿郎
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜, 横浜市
  • Year and Date: 2014-11-26
• [Presentation] JMJD1A のリン酸化スイッチは SWI/SNF および PPARg と複合体を形成しクロマチンの高次構造を変化させる (2014)
  • Author(s): 阿部 陽平, Royhan Rozqie, 松村 欣宏, 川村 猛, 仲木 竜, 鶴谷 悠也, 稲垣 (谷村) 恭子, 塩野 陽, 馬郡 健太, 田中 十志也, 児玉 龍彦, 油谷 浩幸, 稲垣 毅, 酒井 寿郎
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜, 横浜市
  • Year and Date: 2014-11-26
• [Presentation] PKA-dependent Phosphorylation of JMJD1A drives Energy Expenditure through Higher-Order Chromatin Regulation via SWI/SNF and PPARγ Association in Brown Adipocytes (2014)
  • Author(s): Juro Sakai
  • Organizer: The 87th Annual Meeting of the Japanese Biochemical Society
  • Place of Presentation: Kyoto International Conference Center, Kyoto
  • Year and Date: 2014-10-18
  • Invited
• [Presentation] Metabolic and environmental regulations of JmjC histone demethylases (2014)
  • Author(s): Juro Sakai
  • Organizer: The 14th Annual Meeting of the Protein Science Society of Japan
  • Place of Presentation: Workpia Yokohama
  • Year and Date: 2014-06-27
  • Invited
• [Presentation] 交感神経刺激による脂肪燃焼と肥満におけるエピゲノム変化の役割 (2014)
  • Author(s): 酒井寿郎
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡国際会議場, 福岡市
  • Year and Date: 2014-04-24
  • Invited
• [Presentation] PKA-dependent phosphorylation of JMJD1A drives energy expenditure through Higher-Order Chromatin Regulation via SWI/SNF and PPARγ Association in Brown AdipocytesBiology. (2014)
  • Author(s): Juro Sakai
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Miyakomesse, Kyoto
  • Year and Date: 2014-04-15
  • Int'l Joint Research / Invited
• [Presentation] Metabolic and environmental regulations of JmjC histone demethylases (2014)
  • Author(s): Juro Sakai
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Miyakomesse, Kyoto, Japan
  • Year and Date: 2014-04-14
  • Int'l Joint Research
• [Book] エピジェネティクスの産業応用 (2014)
  • Author(s): 酒井寿郎
  • Total Pages: 12
  • Publisher: シーエムシー出版
• [Remarks] 東京大学先端科学技術研究センター酒井研究室/原著論文
  • URL: http://www.mm.rcast.u-tokyo.ac.jp/publications/pubs.html