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

TL;DR

This study shows that the CHD8 protein is crucial for blood cell development in zebrafish embryos by controlling cell survival and inflammation.

Contribution

The study identifies a dual regulatory role of CHD8 in hematopoietic stem and progenitor cell development through p53 and BRD4 pathways.

Findings

CHD8 deficiency causes HSPC depletion via p53-dependent apoptosis.

CHD8 loss leads to BRD4 upregulation and increased cytokine expression.

Inhibiting BRD4 restores HSPC development and reduces inflammation.

Abstract

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 chd8 loss severely depletes the HSPC pool in the caudal hematopoietic tissue through a p53-dependent apoptotic mechanism. Furthermore, chd8−/− embryos exhibit a p53-independent expansion of myelopoiesis. chd8 deficiency upregulates brd4, which promotes systemic inflammatory cytokine expression. Inhibiting brd4 alleviates cytokine expression, suppresses excessive myelopoiesis, and restores HSPC development. Our findings reveal a dual regulatory mechanism in which chd8 governs HSPC development by repressing p53-mediated apoptosis and constraining brd4-driven immune cell differentiation.

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