Molecular mechanisms of a functional linkage between epigenome and mitochondria, and its pathophysiological association

• Project/Area Number: 15H04707
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kumamoto University
• Principal Investigator: NAKAO MITSUYOSHI 熊本大学, 発生医学研究所, 教授 (00217663)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: エピゲノム / ミトコンドリア / 遺伝子 / クロマチン / 代謝

Outline of Final Research Achievements

This study focuses on investigating novel regulatory mechanisms and molecules which functionally link between epigenome and mitochondria. Using specific siRNA libraries and some cell lines, we examined cellular phenotypes, molecular function, RNA-Seq and ChIP-Seq to identify target genes of epigenetic factors. Especially, the lysine methylase SETD8/PR-Set7, which mono-methylates H4K20, was involved in senescence-associated metabolic remodeling, by controlling expression of genes related to nucleolus and mitochondria in human fibroblasts. Further, the lysine demethylase LSD1, a nuclear enzyme which utilizes the flavin adenosine dinucleotide as a cofactor, regulated differentiation and energy metabolism in mouse myoblasts. Inhibition of LSD1 resulted in gene activation for slow twitch fiber differentiation and energy metabolism. These indicate that the epigenetic factors have an essential role in mitochondrial metabolism in various cellular types and conditions.

Research Products

• [Int'l Joint Research] Leicester大学/Imperial College, London/Cambridge大学(英国)
• [Int'l Joint Research] Cologne大学(ドイツ)
• [Int'l Joint Research] 国立衛生学研究所NIH/Texas大学(米国)
• [Int'l Joint Research] Ningbo大学(中国)
• [Int'l Joint Research] Novartis Pharma AG(スイス)
• [Int'l Joint Research] 国立衛生学研究所NIH(米国)
• [Int'l Joint Research] Ningbo大学/Harbin医科大学(中国)
• [Int'l Joint Research] Cambridge大学/Leicester大学(英国)
• [Int'l Joint Research] Cologne大学(ドイツ)
• [Int'l Joint Research] 国立衛生学研究所(米国)
• [Int'l Joint Research] Ningbo大学(中国)
• [Journal Article] LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation (2018)
  • Author(s): K. Anan, S. Hino, N. Shimizu, A. Sakamoto, K. Nagaoka, R. Takase, K. Kohrogi, H. Araki, Y. Hino, S. Usuki, S. Oki, H. Tanaka, K. Nakamura, F. Endo, and M. Nakao
  • Journal Title: Nucleic Acids Res. Volume: 18 Issue: 11 Pages: 5441-5454
  • DOI: 10.1093/nar/gky234
  • Peer Reviewed / Open Access
• [Journal Article] Ki-67 and condensins support the integrity of mitotic chromosomes through distinct mechanisms (2018)
  • Author(s): Takagi Masatoshi、Ono Takao、Natsume Toyoaki、Sakamoto Chiyomi、Nakao Mitsuyoshi、Saitoh Noriko、Kanemaki Masato T.、Hirano Tatsuya、Imamoto Naoko
  • Journal Title: Journal of Cell Science Volume: 131 Pages: 212092-212092
  • DOI: 10.1242/jcs.212092
  • Peer Reviewed / Open Access
• [Journal Article] Maternal undernutrition during early pregnancy inhibits postnatal growth of the tibia in the female offspring of rats by alteration of chondrogenesis (2018)
  • Author(s): Kimura Tomoko、Hino Kodai、Kono Tadaaki、Takano Atsushi、Nitta Norihisa、Ushio Noritoshi、Hino Shinjiro、Takase Ryuta、Kudo Motoi、Daigo Yataro、Morita Wataru、Nakao Mitsuyoshi、Nakatsukasa Masato、Tamagawa Toshihiro、Rafiq Ashiq Mahmood、Matsumoto Akihiro、Otani Hiroki、Udagawa Jun
  • Journal Title: General and Comparative Endocrinology Volume: 260 Issue: 1 Pages: 58-66
  • DOI: 10.1016/j.ygcen.2017.12.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nrf2 promotes oesophageal cancer cell proliferation via metabolic reprogramming and detoxification of reactive oxygen species. (2018)
  • Author(s): Kitano Y, Baba Y, Nakagawa S, Miyake K, Iwatsuki M, Ishimoto T, Yamashita YI, Yoshida N, Watanabe M, Nakao M, Baba H.
  • Journal Title: J Pathol. Volume: 244(3) Issue: 3 Pages: 346-357
  • DOI: 10.1002/path.5021
  • Peer Reviewed / Open Access
• [Journal Article] Condensin II plays an essential role in reversible assembly of mitotic chromosomes in situ (2017)
  • Author(s): Ono Takao、Sakamoto Chiyomi、Nakao Mitsuyoshi、Saitoh Noriko、Hirano Tatsuya
  • Journal Title: Molecular Biology of the Cell Volume: 28 Issue: 21 Pages: 2875-2886
  • DOI: 10.1091/mbc.e17-04-0252
  • Peer Reviewed / Open Access
• [Journal Article] A novel inhibitor of farnesyltransferase with a zinc site recognition moiety and a farnesyl group. (2017)
  • Author(s): Tanaka, A., Radwan, M.O., Hamasaki, A., Ejima, A., Obata, E., Koga, R., Tateishi, H., Okamoto, Y., Fujita, M., Nakao, M., Umezawa, K., Tamanoi, F., and Otsuka, M.
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 27 Issue: 16 Pages: 3862-3866
  • DOI: 10.1016/j.bmcl.2017.06.047
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correlation between Histone Acetylation and Expression of Notch1 in Human Lung Carcinoma and Its Possible Role in Combined Small Cell Lung Carcinoma. (2017)
  • Author(s): Hassan, W., Takebayashi, S. I., Abdalla, M. O., Fujino, K., Kudoh, S., Motooka, Y., Sato, Y., Naito, Y., Higaki, K., Wakimoto, J., Okada, S., Nakao, M., Ishikawa, Y., and Ito, T.
  • Journal Title: Lab. Invest. Volume: 印刷中 Issue: 8 Pages: 913-921
  • DOI: 10.1038/labinvest.2017.36
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to Prevent Senescence-Associated Metabolic Remodeling. (2017)
  • Author(s): Tanaka, H., Takebayashi S. I., Sakamoto, A., Igata, T., Nakatsu, Y., Saitoh, N., Hino, S., and Nakao, M.
  • Journal Title: Cell Rep. Volume: 18 Issue: 9 Pages: 2148-2161
  • DOI: 10.1016/j.celrep.2017.02.021
  • Peer Reviewed / Open Access
• [Journal Article] The glucocorticoid receptor regulates the ANGPTL4 gene in a CTCF-mediated chromatin context in human hepatic cells (2017)
  • Author(s): M. Nakamoto, K. Ishihara, T. Watanabe, A. Hirosue, S. Hino, M. Shinohara, H. Nakayama, and M. Nakao.
  • Journal Title: PLoS One Volume: 12 Issue: 1 Pages: e0169225-e0169225
  • DOI: 10.1371/journal.pone.0169225
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Analysis of estrogen receptor beta gene methylation in autistic males in a Chinese Han population (2017)
  • Author(s): Wang, X., Liang, S., Sun, Y., Li, H., Endo, F., Nakao, M., Saitoh, N.* and Wu, L.*
  • Journal Title: Metab Brain Dis Volume: - Issue: 4 Pages: 1033-1042
  • DOI: 10.1007/s11011-017-9990-7
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] DNA methylation-independent removable insulator controls chromatin remodeling at the HOXA gene locus via retinoic acid signaling (2016)
  • Author(s): K. Ishihara, M. Nakamoto, and M. Nakao.
  • Journal Title: Hum. Mol. Genet. Volume: 25 Pages: 5383-5394
  • DOI: 10.1093/hmg/ddw354
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Potential neuroprotective effects of an LSD1 inhibitor in retinal ganglion cells via p38 MAPK-gamma activity (2016)
  • Author(s): T. Tsutsumi, K. Iwao, H. Hayashi, T. Kawaji, T. Inoue, S. Hino, M. Nakao, and H. Tanihara.
  • Journal Title: Invest. Ophthalmol. Vis. Sci. Volume: 57 Issue: 14 Pages: 6461-6473
  • DOI: 10.1167/iovs.16-19494
  • Peer Reviewed / Open Access
• [Journal Article] UHRF1 regulates global DNA hypomethylation and is associated with poor prognosis in esophageal squamous cell carcinoma (2016)
  • Author(s): K. Nakamura, Y. Baba, K. Kosumi, K. Harada, H. Shigaki, K. Miyake, Y. Kiyozumi, M. Ohuchi, J. Kurashige, T. Ishimoto, M. Iwatsuki, Y. Sakamoto, N. Yoshida, M. Watanabe, M. Nakao, and H. Baba.
  • Journal Title: Oncotarget Volume: 7 Issue: 36 Pages: 57821-57831
  • DOI: 10.18632/oncotarget.11067
  • Peer Reviewed / Open Access
• [Journal Article] Lysine-specific demethylase-1 contributes to malignant behavior by regulation of invasive activity and metabolic shift in esophageal cancer (2016)
  • Author(s): Kosumi K, Baba Y, Sakamoto Y, Ishimoto T, Harada K, Nakamura K, Kurashige J, Hiyoshi Y, Iwatsuki M, Iwagami S, Sakamoto Y, Miyamoto Y, Yoshida N, Oki E, Watanabe M, Hino S, Nakao M, Baba H
  • Journal Title: Int J Cancer Volume: 138 Issue: 2 Pages: 428-39
  • DOI: 10.1002/ijc.29714
  • Peer Reviewed / Open Access
• [Journal Article] Loss of the integral nuclear envelope protein SUN1 induces alteration of nucleoli (2016)
  • Author(s): Matsumoto A, Sakamoto C, Matsumori H, Katahira J, Yasuda Y, Yoshidome K, Tsujimoto M, Goldberg IG, Matsuura N, Nakao M, Saitoh S, Hieda M
  • Journal Title: Nucleus Volume: 7(1) Issue: 1 Pages: 68-83
  • DOI: 10.1080/19491034.2016.1149664
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Nuclear extrusion precedes discharge of genomic DNA fibers during tunicamycin-induced neutrophil extracellular trap-osis (NETosis)-like cell death in cultured human leukemia cells (2016)
  • Author(s): Nakayama, T., Saitoh, N, Morotomi-Yano, K., Yano, K.I., Nakao, M, Saitoh, H
  • Journal Title: Cell Biol Int Volume: 印刷中 Issue: 5 Pages: 597-602
  • DOI: 10.1002/cbin.10594
  • Peer Reviewed
• [Journal Article] HMGA2 promotes adipogenesis by activating C/EBPβ-mediated expression of PPARγ (2016)
  • Author(s): Y. Xi, W. Shen, L. Ma, M. Zhao, J. Zheng, S. Bu, S. Hino, and M. Nakao.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 472 Issue: 4 Pages: 617-623
  • DOI: 10.1016/j.bbrc.2016.03.015
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Retinoblastoma protein promotes oxidative phosphorylation through up-regulation of glycolytic genes in oncogene-induced senescent cells (2015)
  • Author(s): S. Takebayashi, H. Tanaka, S. Hino, Y. Nakatsu, T. Igata, A. Sakamoto, M. Narita, and M. Nakao.
  • Journal Title: Aging Cell Volume: 14 Issue: 4 Pages: 689-697
  • DOI: 10.1111/acel.12351
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The actin family protein ARP6 contributes to the structure and the function of the nucleolus (2015)
  • Author(s): Kitamura, H., Matsumori, H., Kalendova, A., Hozak, P., Goldberg, I.G., Nakao, M., Saitoh, N., Harata, M
  • Journal Title: BBRC Volume: 464 Issue: 2 Pages: 554-560
  • DOI: 10.1016/j.bbrc.2015.07.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A cluster of non-coding RNAs activates the ESR1 locus during breast cancer adaptation to hormone deprivation (2015)
  • Author(s): S. Tomita, M.O. Abdalla, S. Fujiwara, H. Matsumori, K. Maehara, Y. Ohkawa, H. Iwase, N. Saitoh, and M. Nakao.
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 6966-6966
  • DOI: 10.1038/ncomms7966
  • 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 Issue: 4 Pages: 584-596
  • DOI: 10.1016/j.molcel.2015.10.025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lysine demethylase LSD1 coordinates glycolytic and mitochondrial metabolism in hepatocellular carcinoma cells. (2015)
  • Author(s): Sakamoto A, Hino S, Nagaoka K, Anan K, Takase R, Matsumori H, Ojima H, Kanai Y, Arita K, Nakao M
  • Journal Title: Cancer Research Volume: 75(7) Issue: 7 Pages: 1445-1456
  • DOI: 10.1158/0008-5472.can-14-1560
  • Peer Reviewed / Open Access
• [Presentation] 乳がんのホルモン療法抵抗性の機序と治療ポテンシャル (2018)
  • Author(s): 中尾光善、斉藤典子
  • Organizer: 日本がん分子標的治療学会・第13回TRワークショップ
  • Invited
• [Presentation] 細胞老化におけるエネルギー代謝制御機構の解明 (2017)
  • Author(s): 田中宏、竹林慎一郎、坂元顕久、井形朋香、斉藤典子、日野信次朗、中尾光善
  • Organizer: 第40回日本分子生物学会年会・第90回日本生化学会大会
  • Invited
• [Presentation] ヒストン脱メチル化酵素 LSD1による酸素環境応答と代謝可塑性 (2017)
  • Author(s): 日野信次朗、阿南浩太郎、高瀬隆太、興梠健作、中尾光善
  • Organizer: 第40回日本分子生物学会年会・第90回日本生化学会大会
  • Invited
• [Presentation] 活性染色体ドメインに関する核内長鎖ノンコーディングRNA (2017)
  • Author(s): 斉藤典子、山本達郎、Mohamed Abdalla、藤原沙織、冨田さおり、前原一満、大川恭行、立和名博昭、中尾光善
  • Organizer: 第40回日本分子生物学会年会・第90回日本生化学会大会
  • Invited
• [Presentation] ヒストン脱メチル化酵素LSD1の白血病代謝における役割 (2017)
  • Author(s): 興梠健作、日野信次朗、阿南浩太郎、高瀬隆太、中尾光善
  • Organizer: 第40回日本分子生物学会年会・第90回日本生化学会大会
  • Invited
• [Presentation] ヒストン脱メチル化酵素LSD2による脂肪細胞分化制御 (2017)
  • Author(s): 高瀬隆太、日野信次朗、阿南浩太郎、興梠健作、田中宏、中尾光善
  • Organizer: 第40回日本分子生物学会年会・第90回日本生化学会大会
  • Invited
• [Presentation] ステロイドホルモンとエピゲノム記憶 (2017)
  • Author(s): 中尾光善
  • Organizer: 第25回日本ステロイドホルモン学会学術集会
  • Invited
• [Presentation] エネルギー代謝とエピジェネティクス (2017)
  • Author(s): 中尾光善
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] エピジェネティクスと代謝メモリー (2017)
  • Author(s): 中尾光善
  • Organizer: 第55回日本糖尿病学会九州地方会
  • Invited
• [Presentation] クロマチンと核内構造体による細胞制御とがん関連性 (2017)
  • Author(s): 中尾光善、斉藤典子、田中宏
  • Organizer: 第76回日本癌学会学術総会
  • Int'l Joint Research / Invited
• [Presentation] ヒトレトロウイルスHTLV-1は異所性CTCF結合部位をヒトゲノムに挿入する (2017)
  • Author(s): 佐藤賢文、中尾光善、バンガム・チャールズ
  • Organizer: 第76回日本癌学会学術総会
  • Int'l Joint Research / Invited
• [Presentation] 乳がんのホルモン療法抵抗性のエピジェネティック制御 (2017)
  • Author(s): 中尾光善、斉藤典子
  • Organizer: 第54回日本臨床分子医学会学術集会
  • Invited
• [Presentation] エピジェネティクスとエネルギー代謝 (2016)
  • Author(s): 中尾光善、日野信次朗
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜、横浜市
  • Invited
• [Presentation] エピジェネティクスと現代人の体質学 (2016)
  • Author(s): 中尾光善
  • Organizer: 第56回リンパ網内系学会総会・第26回日本樹状細胞研究会
  • Place of Presentation: ホテル日航熊本、熊本市
  • Invited
• [Presentation] 代謝メモリー（DOHaD説）を科学する (2016)
  • Author(s): 中尾光善
  • Organizer: 第52回日本周産期・新生児医学会学術集会
  • Place of Presentation: 富山国際会議場、富山市
  • Invited
• [Presentation] 細胞老化に関わるエピゲノム因子の探索と解析 (2016)
  • Author(s): 中尾光善
  • Organizer: 第43回日本毒性学会学術年会
  • Place of Presentation: ウインクあいち、名古屋市
  • Invited
• [Presentation] エネルギー代謝とエピジェネティクス (2016)
  • Author(s): 中尾光善
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都国際会議場、京都市
  • Invited
• [Presentation] エピジェネティクス（生命のプログラム）の基礎 (2016)
  • Author(s): 中尾光善
  • Organizer: 第119回日本小児科学会学術集会
  • Place of Presentation: ロイトン札幌、札幌市
  • Invited
• [Presentation] マルチオミックス解析技術を用いた代謝－エピゲノムクロストークの解明 (2015)
  • Author(s): 日野信次朗、坂元顕久、長岡克弥、阿南浩太郎、高瀬隆太、興梠健作、中尾光善
  • 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
  • Place of Presentation: ポートアイランド、神戸市
  • Year and Date: 2015-12-02
  • Invited
• [Presentation] Epigenetic reprogramming in physiology and cancer (2015)
  • Author(s): M. Nakao
  • Organizer: The 6th Hiroshima Conference and 50th Anniversary Commemoration
  • Place of Presentation: 広島国際会議場、広島市
  • Year and Date: 2015-10-24
  • Int'l Joint Research / Invited
• [Presentation] 環境エピゲノムによるエネルギー代謝調節と病態 (2015)
  • Author(s): 中尾光善
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル、東京
  • Year and Date: 2015-10-15
  • Invited
• [Presentation] A cluster of non-coding RNAs, Eleanors, activate the ESR1 locus in therapy-resistant breast cancer cells (2015)
  • Author(s): M. Nakao and N. Saitoh
  • Organizer: The 40th Naito Conference on Epigenetics-From histone code to therapeutic strategy
  • Place of Presentation: CHÂTERAISÉ Gateaux Kingdom SAPPORO, 札幌市
  • Year and Date: 2015-09-17
  • Int'l Joint Research / Invited
• [Presentation] エピジェネティクス機構による代謝制御と病態 (2015)
  • Author(s): 中尾光善、坂元顕久、長岡克弥、日野信次朗
  • Organizer: 第88回日本内分泌学会学術集会
  • Place of Presentation: ホテルニューオータニ東京、東京
  • Year and Date: 2015-04-25
  • Invited
• [Book] 環境とエピゲノム―からだは環境によって変わるのか？― (2018)
  • Author(s): 中尾光善
  • Total Pages: 192
  • Publisher: 丸善出版
  • ISBN: 4621302728
• [Book] 実験医学別冊（がん不均一性を理解し、治療抵抗性に挑む がんはなぜ進化するのか？再発するのか？） (2017)
  • Author(s): 藤原沙織、中尾光善
  • Total Pages: 199
  • Publisher: 羊土社
  • ISBN: 4758103682
• [Book] 実験医学別冊（エピジェネティクス実験スタンダード） (2017)
  • Author(s): 石原宏、中尾光善
  • Total Pages: 394
  • Publisher: 羊土社
  • ISBN: 475810199X
• [Book] 実験医学増刊（遺伝子制御の新たな主役 栄養シグナル）（分担執筆） (2016)
  • Author(s): 日野信次朗、阿南浩太郎、高瀬隆太、興梠健作、中尾光善
  • Total Pages: 230
  • Publisher: 羊土社
• [Book] Bio Clinica（エピゲノムの遺伝）（分担執筆） (2016)
  • Author(s): 興梠健作、日野信次朗、中尾光善
  • Total Pages: 114
  • Publisher: 北隆館
• [Book] あなたと私はどうして違う？ 体質と遺伝子のサイエンス－99.9％同じ設計図から個性と病気が生じる秘密 (2015)
  • Author(s): 中尾光善
  • Total Pages: 221
  • Publisher: 羊土社
• [Book] ドライシンドロームの基礎と臨床（分担執筆） (2015)
  • Author(s): 中元雅史、森山雅文、石原 宏、中尾光善
  • Total Pages: 201
  • Publisher: メディカルレビュー社
• [Remarks] 熊本大学発生医学研究所
  • URL: http://www.imeg.kumamoto-u.ac.jp
• [Patent(Industrial Property Rights)] 神経変性疾患治療剤 (2016)
  • Inventor(s): 谷原秀信、岩尾圭一郎、中尾光善、林秀樹、日野信次朗、 堤孝之
  • Industrial Property Rights Holder: 熊本大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-011705
  • Filing Date: 2016-01-25
• [Funded Workshop] International Symposium on Nuclear Structure and Epigenetics (2015)
  • Place of Presentation: 熊本大学発生医学研究所（熊本市）
  • Year and Date: 2015-08-27