TY - JOUR
T1 - MBTD1 preserves adult hematopoietic stem cell pool size and function
AU - Takubo, Keiyo
AU - Htun, Phyo Wai
AU - Ueda, Takeshi
AU - Sera, Yasuyuki
AU - Iwasaki, Masayuki
AU - Koizumi, Miho
AU - Shiroshita, Kohei
AU - Kobayashi, Hiroshi
AU - Haraguchi, Miho
AU - Watanuki, Shintaro
AU - Honda, Zen Ichiro
AU - Yamasaki, Norimasa
AU - Nakamura-Ishizu, Ayako
AU - Arai, Fumio
AU - Motoyama, Noboru
AU - Hatta, Tomohisa
AU - Natsume, Tohru
AU - Suda, Toshio
AU - Honda, Hiroaki
N1 - Publisher Copyright:
Copyright © 2023 the Author(s).
PY - 2023/8/8
Y1 - 2023/8/8
N2 - 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.
AB - 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.
KW - FOXO3a
KW - HSC quiescence
KW - MBTD1 (mbt domain containing 1)
KW - hematopoietic stem cells (HSCs)
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U2 - 10.1073/pnas.2206860120
DO - 10.1073/pnas.2206860120
M3 - Article
C2 - 37523546
AN - SCOPUS:85167843208
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 32
M1 - e2206860120
ER -