Abstract
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.
Highlights
Hematopoietic stem cells (HSCs) remain quiescent for long periods but enter the cell cycle to undergo self-renewal and to produce differentiated blood cells of multiple lineages (Wilson et al, 2008)
Chromodomain helicase DNA-binding protein 8 (CHD8) is essential for HSC maintenance We examined the expression of Chd8 in various hematopoietic cell lineages of wild-type (WT) mice by reverse transcription (RT) and real-time polymerase chain reaction (PCR) analysis
CHD8 mRNA was most abundant in the long-term HSC population, and its abundance declined in association with cell differentiation (Figure 1A)
Summary
Hematopoietic stem cells (HSCs) remain quiescent for long periods but enter the cell cycle to undergo self-renewal and to produce differentiated blood cells of multiple lineages (Wilson et al, 2008). This balance between self-renewal and differentiation is strictly regulated and flexible, ensuring adequate production of blood cells under a variety of physiological conditions while maintaining a stem cell pool (Seita and Weissman, 2010). Members of the CHD family of ATP-dependent chromatin remodelers contain two chromodomains, a helicase/ATPase domain and a DNA binding domain, and play an important role in stem cell maintenance and differentiation through dynamic control of chromatin structure (Micucci et al, 2015). CHD4-deficient HSCs enter the cell cycle and differentiate into the erythroid lineage, but not into the myeloid or lymphoid lineages, resulting in exhaustion of HSCs and progenitors (Yoshida et al, 2008)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
