The Chromatin Remodeler Chd8 Regulates Hematopoietic Stem and Progenitor Cell Survival and Differentiation During Zebrafish Embryogenesis

Chromodomain helicase DNA-binding protein 8 (CHD8), a frequently mutated gene in autism spectrum disorder (ASD), is an ATP-dependent chromatin remodeler with emerging roles in hematopoiesis. While CHD8 is known to maintain hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, its function during developmental hematopoiesis remains undefined. Here, using a zebrafish model, we demonstrate that <i>chd8</i> loss severely depletes the HSPC pool in the caudal hematopoietic tissue through a p53-dependent apoptotic mechanism. Furthermore, <i>chd8</i>^-/- embryos exhibit a p53-independent expansion of myelopoiesis. <i>chd8</i> deficiency upregulates <i>brd4</i>, which promotes systemic inflammatory cytokine expression. Inhibiting <i>brd4</i> alleviates cytokine expression, suppresses excessive myelopoiesis, and restores HSPC development. Our findings reveal a dual regulatory mechanism in which <i>chd8</i> governs HSPC development by repressing p53-mediated apoptosis and constraining <i>brd4</i>-driven immune cell differentiation.