2. Academic Validation
  3. The Chromatin Remodeler Chd8 Regulates Hematopoietic Stem and Progenitor Cell Survival and Differentiation During Zebrafish Embryogenesis

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

  • Int J Mol Sci. 2025 Nov 6;26(21):10805. doi: 10.3390/ijms262110805.
Abrar Ahmed 1,  Xiaona Wei 1,  Dan Zhong 2 3,  Rahat Ullah 1,  Wei Li 1 4,  Lili Jing 1
Affiliations

Affiliations

  • 1 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2 Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), School of Life Science, Shanghai University, Shanghai 200444, China.
  • 3 Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China.
  • 4 Core Facility and Technical Service Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
PMID: 41226840 DOI: 10.3390/ijms262110805
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.

Keywords

Brd4; chromodomain helicase DNA-binding protein 8 (CHD8); hematopoietic stem and progenitor cells (HSPCs); p53; zebrafish.

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