Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling

CHD8 is an ATP-dependent chromatin-remodeling factor whose monoallelic mutation defines a subtype of autism spectrum disorders (ASDs). Previous work found that CHD8 is required for the maintenance of hematopoiesis by integrating ATM-P53-mediated survival of hematopoietic stem/progenitor cells (HSPCs). Here, by using Chd8F/FMx1-Cre combined with a Trp53F/F mouse model that suppresses apoptosis of Chd8−/− HSPCs, we identify CHD8 as an essential regulator of erythroid differentiation. Chd8−/−P53−/− mice exhibited severe anemia conforming to congenital dyserythropoietic anemia (CDA) phenotypes. Loss of CHD8 leads to drastically decreased numbers of orthochromatic erythroblasts and increased binucleated and multinucleated basophilic erythroblasts with a cytokinesis failure in erythroblasts. CHD8 binds directly to the gene bodies of multiple Rho GTPase signaling genes in erythroblasts, and loss of CHD8 results in their dysregulated expression, leading to decreased RhoA and increased Rac1 and Cdc42 activities. Our study shows that autism-associated CHD8 is essential for erythroblast cytokinesis. [Display omitted] •The autism-related chromatin remodeler CHD8 is essential for erythroid differentiation•CHD8 controls erythroblast cytokinesis•Loss of CHD8 causes CDA-like anemia independent of P53 or β-catenin signaling•CHD8 governs the precise balance of Rho GTPase signaling in erythroblasts Tu et al. report that CHD8, an autism-related chromatin remodeler, is essential for erythroid differentiation. Loss of CHD8 leads to unbalanced Rho GTPase signaling and defective erythroblast cytokinesis, mimicking that of congenital dyserythropoietic anemia.