Coupring mechanism of methionine metabolism and epigenome

• Project Area: Crosstalk of transcriptional control and energy pathways by hub metabolites
• Project/Area Number: 23116003
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tohoku University
• Principal Investigator: IGARASHI Kazuhiko 東北大学, 医学(系)研究科(研究院), 教授 (00250738)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥123,318,000 (Direct Cost: ¥94,860,000、Indirect Cost: ¥28,458,000); Fiscal Year 2015: ¥21,099,000 (Direct Cost: ¥16,230,000、Indirect Cost: ¥4,869,000); Fiscal Year 2014: ¥21,099,000 (Direct Cost: ¥16,230,000、Indirect Cost: ¥4,869,000); Fiscal Year 2013: ¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000); Fiscal Year 2012: ¥25,870,000 (Direct Cost: ¥19,900,000、Indirect Cost: ¥5,970,000); Fiscal Year 2011: ¥29,120,000 (Direct Cost: ¥22,400,000、Indirect Cost: ¥6,720,000)
• Keywords: 発現制御 / 発生・分化 / プロテオーム / マイクロアレイ / 免疫学

Outline of Final Research Achievements

Regulation of epigenome relies on methylation of DNA and histones, which utilizes S-adenosyl-L-methoinine (SAM) as a sole methyl donor. SAM is synthesized by methionine adenosyltransferase (MAT) using methionine and ATP as substrates. In this research project, we discovered the molecular mechanism for the nuclear accumulation of MATII, one of the isozyme of MAT in higher eukaryotes. We also found that nuclear MATII interacted with various chromatin and transcription regulators, promoted histone H3 lysine 9 trimethylation of its target genes, and thus repress their expression. MATII also promoted formation of heterochromatin structure of certain chromatin subregions. These observations support our original contention that SAM is synthesized in nuclei for chromatin and gene expression (“local synthesis of SAM for local consumption” model). Next important step will be to understand how the activity of nuclear SAM is regulated during cell differentiation and/or proliferation.

Research Products

• [Int'l Joint Research] Jawaharlal Nehru Center for ASR(インド)
• [Journal Article] Multifunctional human transcriptional coactivator protein PC4 is a substrate of Aurora kinases and activates the Aurora enzymes. (2016)
  • Author(s): Dhanasekaran, K., Kumari, S., Boopathi, R., Shima, H., Swaminathan, A., Bachu, M., Ranga, U., Igarashi, K., and Kundu, T.K.
  • Journal Title: FEBS J. Volume: 283 Issue: 6 Pages: 968-985
  • DOI: 10.1111/febs.13653
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The transcription factor Bach2 is phosphorylated at multiple sites in murine B cells but a single site prevents its nuclear localization (2016)
  • Author(s): Ando R, Shima H, Tamahara T, Sato Y, Watanabe-Matsui M, Kato H, Sax N, Motohashi H, Taguchi K, Yamamoto M, Nio M, Maeda T, Ochiai K, Muto A, Igarashi K
  • Journal Title: J Biol Chem Volume: 291 Issue: 4 Pages: 1826-1840
  • DOI: 10.1074/jbc.m115.661702
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epigenetic Regulation of the Blimp-1 Gene (Prdm1) in B Cells Involves Bach2 and Histone Deacetylase 3* (2016)
  • Author(s): Tanaka H
  • Journal Title: JBC Volume: 291 Issue: 12 Pages: 6316-6330
  • DOI: 10.1074/jbc.m116.713842
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Orchestration of plasma cell differentiation by Bach2 and its gene regulatory network. (2014)
  • Author(s): Igarashi K, Ochiai K, Itoh-Nakadai A, and Muto A.
  • Journal Title: Immunol. Rev. Volume: 261 Issue: 1 Pages: 116-125
  • DOI: 10.1111/imr.12201
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The transcription repressors Bach2 and Bach1 promote B cell development by repressing myeloid program. (2014)
  • Author(s): Itoh-Nakadai A, Hikota R, Muto A, Kometani K, Matsui-Watanabe M, Sato Y, Kobayashi M, Nakamura A, Miura Y, Yano Y, Tashiro S, Sun J, Ikawa T, Ochiai K, Kurosaki T, and Igarashi K.
  • Journal Title: Nature Immunol. Volume: 15 Issue: 12 Pages: 1171-1180
  • DOI: 10.1038/ni.3024
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages. (2014)
  • Author(s): Haldar, M., Kohyama, M., So, A.Y., Kc, W., Wu, X., Briseno, C.G., Satpathy, A.T., Kretzer, N.M., Arase, H., Rajasekaran, N.S., Wang, L., Egawa, T., Igarashi, K., Baltimore, D., Murphy, T.L., and Murphy, K.M.
  • Journal Title: Cell Volume: 156 Issue: 6 Pages: 1223-1234
  • DOI: 10.1016/j.cell.2014.01.069
  • Peer Reviewed
• [Journal Article] Association between BACH2 expression and clinical prognosis in diffuse large B-cell lymphoma. (2014)
  • Author(s): Ichikawa, S., Fukuhara, N., Katsushima, H., Takahashi, T., Yamamoto, J., Yokoyama, H., Sasaki, O., Fukuhara, O., Nomura, J., Ishizawa, K., Ichinohasama, R., Muto, A., Igarashi, K., and Harigae, H.
  • Journal Title: Cancer Science Volume: in press Issue: 4 Pages: 437-444
  • DOI: 10.1111/cas.12361
  • Peer Reviewed / Open Access
• [Journal Article] Hemopexin-dependent heme uptake via endocytosis regulates the Bach1 transcription repressor and heme oxygenase gene activation. (2014)
  • Author(s): Hada, H., Shiraki, T., Watanabe-Matsui, M., and Igarashi, K.
  • Journal Title: Biochimica et Biophysica Acta Volume: in press Issue: 7 Pages: 2351-2360
  • DOI: 10.1016/j.bbagen.2014.02.029
  • Peer Reviewed
• [Journal Article] Methionine adenosyltransferase II-dependent histone H3K9 methylation at the COX-2 gene locus. (2013)
  • Author(s): Kera, Y., Katoh, Y., Ohta, M., Matsumoto, M., Takano-Yamamoto, T. and Igarashi, K.
  • Journal Title: The Journal of Biological Chemistry Volume: 288 Issue: 19 Pages: 12592-13601
  • DOI: 10.1074/jbc.m112.429738
  • Peer Reviewed
• [Journal Article] Bach2 represses effector programmes to stabilize Treg-mediated immune homeostasis. (2013)
  • Author(s): Roychoudhuri, R., Hirahara, K., Mousavi, K., Clever, D., Klebanoff, C. A., Bonelli, M., Sciume, G., Zare, H., Vahedi, G., Dema, B., Yu, Z., Liu, H., Takahashi, H., Rao, M., Muranski, P., Crompton, J. G., Punkosdy, G., Muto, A., Igarashi, K., et al.
  • Journal Title: Nature Volume: 498 Issue: 7455 Pages: 506-510
  • DOI: 10.1038/nature12199
  • Peer Reviewed
• [Journal Article] BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. (2013)
  • Author(s): Swaminathan, S., Huang, C., Geng, H., Chen, Z., Harvey, R., Kang, H., Ng, C., Titz, B., Hurtz, C., Sadiyah, M. F., Nowak, D., Thoennissen, G. B., Rand, V., Graeber, T. G., Koeffler, H. P., Carrooll, W. L. Willman, C. L., Hall, A. G., Igarashi, K., Melnick, A. and Muschen, M.
  • Journal Title: Nature Medicine Volume: 19 Issue: 8 Pages: 1014-1022
  • DOI: 10.1038/nm.3247
  • Peer Reviewed
• [Journal Article] Bach2 maintains T cells in a naive state by suppressing effector memory-related genes (2013)
  • Author(s): Tsukumo, S., Unno, M., Muto, A., Takeuchi, A., Kometani, K., Kurosaki, T., Igarashi, K., Saito, T
  • Journal Title: Proc. Natl. Acad. Sci. U. S. A. Volume: 110 Issue: 26 Pages: 10735-40
  • DOI: 10.1073/pnas.1306691110
  • Peer Reviewed
• [Journal Article] Transforming growth factor-&βinduces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene. (2013)
  • Author(s): Okita Y, Kamoshida A, Suzuki H, Itoh K, Motohashi H, Igarashi K, Ogami T, Koinuma D, Kato M.
  • Journal Title: J Biol Chem Volume: 288 Issue: 28 Pages: 20658-20667
  • DOI: 10.1074/jbc.m113.450478
  • NAID: 120007136878
  • Peer Reviewed
• [Journal Article] Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function (2013)
  • Author(s): Nakamura A, Ebina-Shibuya R, Itoh-Nakadai A, Muto A, Shima H, Saigusa D, Aoki J, Ebina M, Nukiwa T, Igarashi K.
  • Journal Title: J Exp Med. Volume: 210 Issue: 11 Pages: 2191
  • DOI: 10.1084/jem.20130028
  • Peer Reviewed
• [Journal Article] Activation of the SUMO modification system is required for the accumulation of RAD51 at sites containing DNA damage (2013)
  • Author(s): Shima H, Suzuki H, Sun J, Kono K, Shi L, Kinomura A, Horikoshi Y, Ikura T, Ikura M, Kanaar R, Igarashi K, Saitoh H, Kurumizaka H, Tashiro S
  • Journal Title: J Cell Sci Volume: 126 Pages: 5284-5292
  • DOI: 10.1242/jcs.133744
  • Peer Reviewed
• [Journal Article] Methionine adenosyltransferase II-dependent histone H3K9 methylation at the COX-2 gene locus. (2013)
  • Author(s): Kera Y, Katoh Y, Ohta M, Matsumoto M, Takano-Yamamoto T, Igarashi K.
  • Journal Title: J Biol Chem Volume: in press
  • Peer Reviewed
• [Journal Article] Bach1 is critical for the transformation of mouse embryonic fibroblast by RasV12 and maintains ERK signaling (2012)
  • Author(s): Nakanome A, Brydoun A, Matsumoto M, Ota K, Funayama R, Nakayama K, Ono M, Shiga K, Kobayashi T, Igarashi K
  • Journal Title: Oncogene Volume: 32 Issue: 27 Pages: 3231-3245
  • DOI: 10.1038/onc.2012.336
  • Peer Reviewed
• [Presentation] local synthesis of S-adenosylmethionine for local consumption, version 2: methylation of chromatin and beyond. (2016)
  • Author(s): 五十嵐和彦
  • Organizer: 転写代謝システム国際シンポジウム
  • Place of Presentation: 東京大学（東京都文京区）
  • Year and Date: 2016-02-17
  • Int'l Joint Research
• [Presentation] Local production of S-adenosylmethionine for local consumption to promote and to regulate methylation of chromatin and beyond. (2015)
  • Author(s): 五十嵐和彦
  • Organizer: BMB2015（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: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] S-アデノシルメチオニン合成酵素MAT2Aの発現は3' UTRアデニンメチル化が介するmRNA安定性により制御される (2015)
  • Author(s): 島弘季
  • Organizer: BMB2015（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: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] S-アデノシルメチオニンの核内産生機構とそのエピゲノム制御における役割 (2015)
  • Author(s): 五十嵐和彦
  • Organizer: 第26回フォーラム・イン・ドージン
  • Place of Presentation: 熊本ホテルキャッスル（熊本県熊本市）
  • Year and Date: 2015-11-13
  • Invited
• [Presentation] S-アデノシルメチオニン合成酵素のクロマチンRNA制御における機能と肝再生におけるクロマチン転写ネットワーク (2015)
  • Author(s): 五十嵐和彦
  • Organizer: 長崎医学会特別講演
  • Place of Presentation: 長崎大学大学院医歯薬学総合研究科（長崎県長崎市）
  • Year and Date: 2015-09-18
  • Invited
• [Presentation] SAM合成酵素MAT2A mRNA量はメチル-6-アデノシン修飾を介して制御される (2015)
  • Author(s): 島弘季
  • Organizer: 転写代謝システム会議2015 at 熊本
  • Place of Presentation: 菊南温泉ユウベルホテル（熊本県熊本市）
  • Year and Date: 2015-06-14
• [Presentation] The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program. (2015)
  • Author(s): A Ito-Nakadai, A Muto, M Watanabe-Matsui, K Kometani, Y Sato, T Ikawa, K Ochiai, T Kurosaki, K Igarashi
  • Organizer: 2015 Keystone Symposia Conference : The Golden Anniversary of B Cell Discovery
  • Place of Presentation: Fairmont Banff Springs （カナダ、バンフ）
  • Year and Date: 2015-03-22 – 2015-03-27
• [Presentation] Local synthesis of S-adenosylmethionine for local consumption: how metabolism is coupled with epigenomic regulation. (2015)
  • Author(s): Kazuhiko Igarashi
  • Organizer: 5th Meeting of the Asian Forum of Chromosome and Chromatin Biology
  • Place of Presentation: Jawaharlal Nehru Center for Advanced Scientific Research （インド、バンガロール）
  • Year and Date: 2015-01-15 – 2015-01-18
  • Invited
• [Presentation] Contribution of nuclear localized MATIIα to nuclear SAM pool. (2015)
  • Author(s): Masayuki Ebina, Yasutake Katoh, Kazuhiko Igarashi
  • Organizer: 5th Meeting of the Asian Forum of Chromosome and Chromatin Biology
  • Place of Presentation: Jawaharlal Nehru Center for Advanced Scientific Research （インド、バンガロール）
  • Year and Date: 2015-01-15 – 2015-01-18
• [Presentation] The function of methionine adenosyltransferase 2 in plasma cell differentiation. (2014)
  • Author(s): Kazuhiko Igarashi
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] SAM合成酵素の核内局在によるエピゲノムの制御 (2014)
  • Author(s): 五十嵐和彦
  • Organizer: 第二回がんと代謝研究会
  • Place of Presentation: 東京理科大学葛飾キャンパス（東京都葛飾区）
  • Year and Date: 2014-07-10
  • Invited
• [Presentation] Nuclear localization of methionine adenosyltransferase II and its function in B cell response. (2014)
  • Author(s): Kazuhiko Igarashi
  • Organizer: 17th Chromatin Assembly Meeting
  • Place of Presentation: Bangalore, India
  • Invited
• [Presentation] Regulation of B cell activation and differentiation by methionine adenosyltransferase II. (2013)
  • Author(s): Kazuhiko Igarashi
  • Organizer: International Symposium on Transcription and Metabolism
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県淡路市）
  • Invited
• [Presentation] 転写因子―エピゲノムネットワークによる遺伝情報のプログラミング (2013)
  • Author(s): 五十嵐和彦
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 江陽グランドホテル（宮城県仙台市）
  • Invited
• [Presentation] Heme as a signaling molecule for globin gene regulation and iron homeostasis. (2013)
  • Author(s): M.Kobayashi., H.Hada., A.Muto.,H.Harigae. K.Igarashi.
  • Organizer: Cold Spring Harbor Laboratory Meeting Metabolic Sgnaling & Disease:From Cell to Ofganism
  • Place of Presentation: Cold Spring Harbor Laboratory, U.S.A.
  • Invited
• [Presentation] Coupling of metabolism and transcription by a denosylmethionine transferase (2011)
  • Author(s): Kazuhiko Igarashi
  • Organizer: Invited Seminar, Jawaharlal Nehru Center for Advanced Scientific Research, India
  • Place of Presentation: Bangalore、インド
  • Year and Date: 2011-12-23
• [Presentation] Coupling of metabolism and transcription by adenosylmethionine transferase (2011)
  • Author(s): Kazuhiko Igarashi
  • Organizer: Invited Seminar, Institute of Chemical Biology, India
  • Place of Presentation: Kolkata、インド
  • Year and Date: 2011-12-22
• [Presentation] MafK-dependent and -independent nuclear function of methionine adenosyltransferase (2011)
  • Author(s): Kazuhiko Igarashi
  • Organizer: 日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-16
• [Presentation] SAMIT核内モジュールによるSAM合成とヒストンメチル化の共役 (2011)
  • Author(s): 五十嵐和彦
  • Organizer: 日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-22
• [Presentation] 転写因子によるB細胞-形質細胞分化調節ネットワーク
  • Author(s): 五十嵐和彦、落合恭子、加藤恭丈、武藤哲彦
  • Organizer: 国際高等研究所クロマチンデコーディング集会
  • Place of Presentation: 国際高等研究所
  • Invited
• [Book] Epigenetics:Dvelopment and Disease (2012)
  • Author(s): Igarashi K, Katoh Y.
  • Publisher: Springer
• [Book] Epigenetics : Development and Disease (2012)
  • Author(s): Kazuhiko Igarashi, et al
  • Publisher: Springer
• [Remarks] 東北大学大学院医学系研究科生物化学分野ホームページ
  • URL: http://www.biochem.med.tohoku.ac.jp/
• [Remarks] 東北大学大学院医学系研究科生物化学分野ホームページ
  • URL: http://www.biochem.med.tohoku.ac.jp/
• [Remarks] 研究室HP
  • URL: http://www.biochem.med.tohoku.ac.jp/
• [Remarks] 研究室HP
  • URL: http://www.biochem.med.tohoku.ac.jp/