Elucidation of mechanisms underlying stem cell aging induced by deregulation of histone modifications and development of anti-aging therapies by maintaining their functions

• Project/Area Number: 19K22546
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: HONDA HIROAKI 東京女子医科大学, 医学部, 教授 (40245064)
• Co-Investigator(Kenkyū-buntansha): 世良 康如 東京女子医科大学, 医学部, 助教 (40836532) ; 本田 善一郎 お茶の水女子大学, 保健管理センター, 特任教授 (70238814) ; 岩崎 正幸 東京女子医科大学, 医学部, 講師 (70790913)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: Utx / ヒストン脱メチル化酵素 / 幹細胞老化 / Uty / エピジェネティクス / ヒストン脱メチル化 / UTX / UTY / ヒストンメチル化・脱メチル化 / ヒストン修飾 / 幹細胞 / 老化 / 抗加齢療法

Outline of Research at the Start

UTXはX染色体特異的遺伝子であり、ヒストンH3の27番目のリジン残基（H3K27）を脱メチル化する。我々はUTX欠損マウスを作製し、UTXの欠失は造血幹細胞を老化に誘導することを見出した。
この申請では、様々な組織においてUTXを欠損させ、UTX欠失と組織幹細胞老化の分子機構について解明を行う。また、UTX機能維持による老化の遅延・回復について検討し、さらにY染色体上のUTX相補体であるUTY欠失マウスも作製し、男女による老化感受性の違いについても探索を行う。得られた結果は、ヒストン修飾因子を介した老化制御機構に新たな知見をもたらすと共に、新たな抗加齢療法の発展に貢献すると期待される。

Outline of Final Research Achievements

We previously generated mice deficient in UTX, a demethylase for histone H3K27, in the hematopoietic system, and found that hematopoietic cells lacking UTX exhibited cardinal features of hematopoietic stem cell aging. In this study, we generated and analyzed mice lacking UTX in various tissues. We found that mice lacking UTX in the brain exhibited enhanced H3K27 methylation which induced impaired DNA replication, suppressive neuronal differentiation, fetal ventriculomegaly, and neonatal death. In addition, we found that mice lacking UTX in the skin exhibited postnatal alopecia. We are currently analyzing mice lacking UTX in other tissues. In addition, we generated mice that inducibly overexpress Utx and mice lacking Uty, the Utx homologue in the Y chromosome.

Academic Significance and Societal Importance of the Research Achievements

ヒストン脱メチル化酵素UTXは、幹細胞機能維持に重要と考えられているが、その老化における機能は明らかでは無かった。我々は造血系でUTXの欠失マウスを作製し、造血幹細胞老化に特徴的な所見を認めた。この研究では、脳、皮膚、その他の組織特異的なUTX欠失マウスを作製・解析することにより、造血以外の幹細胞機能におけるUTXの役割やその欠失による組織老化のメカニズムが明らかになると考えられる。また、我々は併せて誘導可能にUtxを高発現するマウスおよびUtxのY染色体相補遺伝子であるUtyの欠失マウスも作製した。これらのマウスも、組織幹細胞維持機構やその機能低下による老化機構の解明に役立つと期待される。

Research Products

• [Journal Article] Deletion of epithelial cell-specific p130Cas impairs the maturation stage of amelogenesis (2022)
  • Author(s): Inoue Akane、Kiyoshima Tamotsu、Yoshizaki Keigo、Nakatomi Chihiro、Nakatomi Mitsushiro、Ohshima Hayato、Shin Masashi、Gao Jing、Tsuru Kanji、Okabe Koji、Nakamura Ichiro、Honda Hiroaki、Matsuda Miho、Takahashi Ichiro、Jimi Eijiro
  • Journal Title: Bone Volume: 154 Pages: 116210-116210
  • DOI: 10.1016/j.bone.2021.116210
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The unique function of p130Cas in regulating the bone metabolism (2022)
  • Author(s): Jimi Eijiro、Honda Hiroaki、Nakamura Ichiro
  • Journal Title: Pharmacology and Therapeutics Volume: 230 Pages: 107965-107965
  • DOI: 10.1016/j.pharmthera.2021.107965
  • Peer Reviewed / Open Access
• [Journal Article] Wnt5a plays a critical role in anal opening in mice at an early stage of embryonic development (2022)
  • Author(s): Nakata Mitsuyuki、Honda Hiroaki、Iwama Atsushi、Terui Keita、Komatsu Shugo、Shibata Ryohei、Hishiki Tomoro
  • Journal Title: Pediatric Surgery International Volume: 38 Issue: 5 Pages: 743-747
  • DOI: 10.1007/s00383-022-05103-4
  • Peer Reviewed
• [Journal Article] DEC1 deficiency results in accelerated osteopenia through enhanced DKK1 activity and attenuated PI3KCA/Akt/GSK3β signaling (2021)
  • Author(s): He Shuangcheng、Guan Yu、Wu Yichen、Zhu Ling、Yan Bingfang、Honda Hiroaki、Yang Jian、Liu Wei
  • Journal Title: Metabolism Volume: 118 Pages: 154730-154730
  • DOI: 10.1016/j.metabol.2021.154730
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Progress of genome editing technology and developmental biology useful for radiation research (2021)
  • Author(s): Miura Kento、Ogura Atsuo、Kobatake Kohei、Honda Hiroaki、Kaminuma Osamu
  • Journal Title: Journal of Radiation Research Volume: 62 Issue: Supplement_1 Pages: i53-i63
  • DOI: 10.1093/jrr/rraa127
  • Peer Reviewed / Open Access
• [Journal Article] Pathological Role of Pin1 in the Development of DSS-Induced Colitis (2021)
  • Author(s): Matsunaga Yasuka、Hasei Shun、Yamamotoya Takeshi、Honda Hiroaki、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Ito Hisanaka、Okabe Takayoshi、Asano Tomoichiro、Nakatsu Yusuke
  • Journal Title: Cells Volume: 10 Issue: 5 Pages: 1230-1230
  • DOI: 10.3390/cells10051230
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Loss of H3K27 Histone Demethylase Utx in T Cells Aggravates Allergic Contact Dermatitis (2021)
  • Author(s): Inoue Takashi、Omori-Miyake Miyuki、Maruyama Saho、Okabe Masataka、Kuwahara Makoto、Honda Hiroaki、Miura Hiromasa、Yamashita Masakatsu
  • Journal Title: The Journal of Immunology Volume: 207 Issue: 9 Pages: 2223-2234
  • DOI: 10.4049/jimmunol.2001160
  • Peer Reviewed / Open Access
• [Journal Article] Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway (2021)
  • Author(s): Fujino Takeshi、Goyama Susumu、Sugiura Yuki、Inoue Daichi、Asada Shuhei、Yamasaki Satoshi、Matsumoto Akiko、Yamaguchi Kiyoshi、Isobe Yumiko、Tsuchiya Akiho、Shikata Shiori、Sato Naru、Morinaga Hironobu、Fukuyama Tomofusa、Tanaka Yosuke、Fukushima Tsuyoshi、Takeda Reina、Yamamoto Keita、Honda Hiroaki et al
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 1826-1826
  • DOI: 10.1038/s41467-021-22053-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] UTX maintains functional integrity of murine hematopoietic system by globally regulating aging-associated genes. (2021)
  • Author(s): Sera Y; Nakata Y; Ueda T; Yamasaki N; Koide S; Kobayashi H; Ikeda KI; Kobatake K; Iwasaki M; Oda H; Wolff L; Kanai A; Nagamachi A; Inaba T; Sotomaru Y; Ichinohe T; Koizumi M; Miyakawa Y; Honda ZI; Iwama A; Suda T; Takubo K; Honda H
  • Journal Title: Blood. Volume: 137 Issue: 7 Pages: 908-922
  • DOI: 10.1182/blood.2019001044
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL (2020)
  • Author(s): Atsushi Watanabe, Kunio Miyake, Jessica Nordlund, Ann-Christine Syvanen, Louise van der Weyden, Hiroaki Honda, Norimasa Yamasaki, Akiko Nagamachi, Toshiya Inaba, Tomokatsu Ikawa, Kevin Y Urayama, Nobutaka Kiyokawa, Akira Ohara, Shunsuke Kimura, Yasuo Kubota, Junko Takita, Hiroaki Goto, Kimiyoshi Sakaguchi, et al.
  • Journal Title: Blood Volume: 136 Issue: 20 Pages: 2319-2333
  • DOI: 10.1182/blood.2019004090
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HHEX promotes myeloid transformation in cooperation with mutant ASXL1. (2020)
  • Author(s): Takeda R, Asada S, Park SJ, Yokoyama A, Becker H, Kanai A, Visconte V, Hershberger C, Hayashi Y, Yonezawa T, Tamura M, Fukushima T, Tanaka Y, Fukuyama T, Matsumoto A, Yamasaki S, Nakai K, Yamazaki S, Inaba T, Shibata T, Inoue D, Honda H, Goyama S, Maciejewski J, Kitamura T.
  • Journal Title: Blood Volume: 136 Pages: 1670-1684
  • DOI: 10.1182/blood.2019004613
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Jmjd3 plays pivotal roles in the proper development of early-born retinal lineages, amacrine, horizontal, and retinal ganglion cells. (2020)
  • Author(s): Iwagawa T, Honda H, Watanabe S.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 61 Issue: 11 Pages: 43-43
  • DOI: 10.1167/iovs.61.11.43
  • Peer Reviewed
• [Journal Article] Dual Regulation of Histone Methylation by mTOR Complexes Controls Glioblastoma Tumor Cell Growth via EZH2 and SAM (2020)
  • Author(s): Harachi Mio、Masui Kenta、Honda Hiroaki、Muragaki Yoshihiro、Kawamata Takakazu、Cavenee Webster K.、Mischel Paul S.、Shibata Noriyuki
  • Journal Title: Molecular Cancer Research Volume: 18 Issue: 8 Pages: 1142-1152
  • DOI: 10.1158/1541-7786.mcr-20-0024
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TX regulates the differentiation of a subset of bipolar cells in the mouse retina. (2020)
  • Author(s): Umutoni D, Iwagawa T, Baba Y, Tsuhako A, Honda H, Aihara M, Watanabe S.
  • Journal Title: Genes Cells Volume: 25 Issue: 6 Pages: 402-412
  • DOI: 10.1111/gtc.12767
  • Peer Reviewed / Open Access
• [Journal Article] Accumulation of versican facilitates wound healing: implication of its initial ADAMTS-cleavage site. (2020)
  • Author(s): Islam S, Chuensirikulchai K, Khummuang S, Keratibumrungpong T, Kongtawelert P, Kasinrerk W, Hatano S, Nagamachi A, Honda H, *Watanabe H.
  • Journal Title: Matrix Biol Volume: 87 Pages: 77-93
  • Peer Reviewed
• [Journal Article] Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction (2020)
  • Author(s): Kobatake Kohei et al., Honda Zen-ichiro et al. and Honda Hiroaki
  • Journal Title: Clinical Cancer Research Volume: 26 Issue: 8 Pages: 2065-2079
  • DOI: 10.1158/1078-0432.ccr-19-2230
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The loss of dopaminergic neurons in DEC1 deficient mice potentially involves the decrease of PI3K/Akt/GSK3β signaling. (2019)
  • Author(s): 4.Zhu Z, Yichen W, Ziheng Z, Dighao G, Ming L, Wei L, Enfang S, Gang H, Honda H, Jian Y
  • Journal Title: Aging Volume: 11 Issue: 24 Pages: 12733-12753
  • DOI: 10.18632/aging.102599
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Discrimination of dormant and active hematopoietic stem cells by G0 markers reveals dormancy regulation by cytoplasmic calcium. (2019)
  • Author(s): 5.Fukushima T, Tanaka Y, Hamey FK, Chang CH, Oki T, Asada S, Hayashi Y, Fujino T, Yonezawa T, Takeda R, Kawabata KC, Fukuyama T, Umemoto T, Takubo K, Takizawa H, Goyama S, Ishihama Y, Honda H, Gottgens B, Kitamura T.
  • Journal Title: Cell Rep Volume: 29 Issue: 12 Pages: 4144-4158
  • DOI: 10.1016/j.celrep.2019.11.061
  • NAID: 120006892032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 破骨細胞骨吸収制御因子のshRNAライブラリースクリーニングによる網羅的探索とその候補遺伝子の機能解析 (2021)
  • Author(s): 久木田明子, 平田寛人, 蒲原麻菜, 村山雅俊, 本田浩章, 馬渡正明
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] ヒストン修飾因子UTXは老化関連遺伝子を制御することにより造血系維持に関与する (2021)
  • Author(s): 世良康如, 中田雄一郎, 上田健, 山崎憲政, 小出周平, 小林央, 池田健一郎, 小畠浩平, 岩崎正幸, 小田秀明, 金井昭教, 長町安希子, 稲葉俊哉, 外丸祐介, 一戸辰夫, 小泉美穂, 宮川佳彦, 本田善一郎, 岩間厚志, 須田年生, 田久保圭誉, 本田浩章
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] Wnt5a plays a critical role in anal opening at an early stage of embryo development (2021)
  • Author(s): Mitsuyuki Nakata, Hiroaki Honda, Atsushi Iwama, Keita Teru1, Shugo Komatsu, Ryohei Shibata, Tomoro Hishiki
  • Organizer: 34th International Symposium on Pediatric Surgical Research
  • Int'l Joint Research
• [Presentation] 1.膀胱がん発症におけるヒストン修飾因子KDM6Aの機能解析 (2020)
  • Author(s): 本田浩章
  • Organizer: 国立がんセンター鶴岡カンファランス
  • Invited
• [Presentation] 2.ヒストン修飾因子UTXは老化関連遺伝子を制御することにより造血形維持に関与する (2020)
  • Author(s): 世良康如, 本田浩章
  • Organizer: 第1回レドックスR&D戦略研究会
  • Invited
• [Presentation] MLL遺伝子再構成を伴う急性骨髄性白血病幹細胞における15－PGDHの役割 (2019)
  • Author(s): 岩崎正幸、本田浩章、大里元美、Michael Cleary
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] ヒストン脱メチル化酵素JMJD3が白血病を誘導させるエピゲノム制御および蛋白質相互作用の解明 (2019)
  • Author(s): 中田雄一郎、上田健、金井昭教、世良康如、竹田浩之、神沼修、本田浩章
  • Organizer: 第92回日本生化学会大会
• [Presentation] ヒストンの修飾因子UTXの脳特異的な欠損マウスの解析 (2019)
  • Author(s): 小泉美穂、三田村佳勇、世良康如、本田浩章、衛藤光、岸雄介、藤平篤志
  • Organizer: 第42回日本分子生物学会
• [Remarks]
  • URL: https://www.twmu.ac.jp/ILA/
• [Remarks] 東京女子医科大学・実験動物研究所
  • URL: http://www.twmu.ac.jp/ILA/