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MBTD1 preserves adult hematopoietic stem cell pool size and function.
Takubo, Keiyo; Htun, Phyo Wai; Ueda, Takeshi; Sera, Yasuyuki; Iwasaki, Masayuki; Koizumi, Miho; Shiroshita, Kohei; Kobayashi, Hiroshi; Haraguchi, Miho; Watanuki, Shintaro; Honda, Zen-Ichiro; Yamasaki, Norimasa; Nakamura-Ishizu, Ayako; Arai, Fumio; Motoyama, Noboru; Hatta, Tomohisa; Natsume, Tohru; Suda, Toshio; Honda, Hiroaki.
Affiliation
  • Takubo K; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
  • Htun PW; Medical Department, 7887 Healthcare Call Center, Yangon 11062, Myanmar.
  • Ueda T; Department of Biochemistry, Kindai University Faculty of Medicine, Sayama-shi, Osaka 589-8511, Japan.
  • Sera Y; Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-8666, Japan.
  • Iwasaki M; Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-8666, Japan.
  • Koizumi M; Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-8666, Japan.
  • Shiroshita K; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
  • Kobayashi H; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
  • Haraguchi M; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
  • Watanuki S; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
  • Honda ZI; Health Care Center and Graduate School of Humanities and Sciences, Institute of Environmental Science for Human Life, Ochanomizu University, Bunkyo-ku, Tokyo 112-8611, Japan.
  • Yamasaki N; Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan.
  • Nakamura-Ishizu A; Department of Microscopic and Developmental Anatomy, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
  • Arai F; Department of Stem Cell Biology and Medicine, Graduate School of Medical Science, Kyusyu University, Fukuoka 812-8582, Japan.
  • Motoyama N; Department of Human Nutrition, Sugiyama Jogakuen University School of Life Studies, Nagoya 464-8662, Japan.
  • Hatta T; Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
  • Natsume T; Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
  • Suda T; Cancer Science Institute of Singapore, National University of Singapore Center for Translational Medicine, Singapore 117599, Singapore.
  • Honda H; Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-8666, Japan.
Proc Natl Acad Sci U S A ; 120(32): e2206860120, 2023 08 08.
Article in En | MEDLINE | ID: mdl-37523546
ABSTRACT
Mbtd1 (mbt domain containing 1) encodes a nuclear protein containing a zinc finger domain and four malignant brain tumor (MBT) repeats. We previously generated Mbtd1-deficient mice and found that MBTD1 is highly expressed in fetal hematopoietic stem cells (HSCs) and sustains the number and function of fetal HSCs. However, since Mbtd1-deficient mice die soon after birth possibly due to skeletal abnormalities, its role in adult hematopoiesis remains unclear. To address this issue, we generated Mbtd1 conditional knockout mice and analyzed adult hematopoietic tissues deficient in Mbtd1. We observed that the numbers of HSCs and progenitors increased and Mbtd1-deficient HSCs exhibited hyperactive cell cycle, resulting in a defective response to exogenous stresses. Mechanistically, we found that MBTD1 directly binds to the promoter region of FoxO3a, encoding a forkhead protein essential for HSC quiescence, and interacts with components of TIP60 chromatin remodeling complex and other proteins involved in HSC and other stem cell functions. Restoration of FOXO3a activity in Mbtd1-deficient HSCs in vivo rescued cell cycle and pool size abnormalities. These findings indicate that MBTD1 is a critical regulator for HSC pool size and function, mainly through the maintenance of cell cycle quiescence by FOXO3a.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Bone Marrow / Hematopoietic Stem Cells Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2023 Document type: Article Affiliation country: Japón
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Bone Marrow / Hematopoietic Stem Cells Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2023 Document type: Article Affiliation country: Japón