The autism-related protein CHD8 contributes to the stemness and differentiation of mouse hematopoietic stem cells

Chromodomain helicase DNA-binding protein 8 (CHD8) is an ATP-dependent chromatin-remodeling factor that is encoded by the most frequently mutated gene in individuals with autism spectrum disorder. CHD8 is expressed not only in neural tissues but also in many other organs; however, its functions are largely unknown. Here, we show that CHD8 is highly expressed in and maintains the stemness of hematopoietic stem cells (HSCs). Conditional deletion of Chd8 specifically in mouse bone marrow induces cell cycle arrest, apoptosis, and a differentiation block in HSCs in association with upregulation of the expression of p53 target genes. A colony formation assay and bone marrow transplantation reveal that CHD8 deficiency also compromises the stemness of HSCs. Furthermore, additional ablation of p53 rescues the impaired stem cell function and differentiation block of CHD8-deficient HSCs. Our results thus suggest that the CHD8-p53 axis plays a key role in regulation of the stemness and differentiation of HSCs. [Display omitted] •CHD8 is expressed at a high level in hematopoietic stem cells (HSCs)•CHD8 loss induces cell cycle arrest, apoptosis, and a differentiation block in HSCs•CHD8 deficiency compromises HSC stemness through activation of p53 target genes•Additional ablation of p53 in CHD8-deficient HSCs restores stem cell function Nita et al. reveal that the CHD8-p53 axis plays a key role in regulation of the stemness and differentiation of hematopoietic stem cells (HSCs) in vitro and in vivo. CHD8 deficiency in HSCs results in cell cycle arrest, apoptosis, and a differentiation block, which are partially rescued by additional deletion of p53.