MBTD1 preserves adult hematopoietic stem cell pool size and function.

Abstract

<i>Mbtd1 (mbt domain containing 1</i>) encodes a nuclear protein containing a zinc finger domain and four malignant brain tumor (MBT) repeats. We previously generated <i>Mbtd1</i>-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 <i>Mbtd1</i>-deficient mice die soon after birth possibly due to skeletal abnormalities, its role in adult hematopoiesis remains unclear. To address this issue, we generated <i>Mbtd1</i> conditional knockout mice and analyzed adult hematopoietic tissues deficient in <i>Mbtd1</i>. We observed that the numbers of HSCs and progenitors increased and <i>Mbtd1</i>-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 <i>FoxO3a</i>, 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 <i>Mbtd1-</i>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.