A study led by Prof. LIU Feng from the Institute of Zoology of the Chinese Academy of Sciences has identified a crucial role for the tryptophan-aspartic acid (WD) repeat protein 5 (Wdr5) in maintaining the survival and genomic integrity of hematopoietic stem and progenitor cells (HSPCs) during embryonic development. The findings were published in Proceedings of the National Academy of Sciences (PNAS).

HSPCs are the foundational "seed cells" of the blood system. They emerge in the aorta-gonad-mesonephros region during early embryogenesis and subsequently migrate to the caudal hematopoietic tissue, which is comparable to the mammalian fetal liver. In this location, they undergo rapid proliferation. However, this intense replication phase makes HSPCs susceptible to DNA damage and genomic instability.

In this study, using zebrafish as a model organism, the researchers discovered that Wdr5 functions as a genomic guardian by regulating a specific epigenetic mark—H3K4 methylation. When Wdr5 was disabled, the number of HSPCs dropped significantly, leading to widespread DNA damage and cell death.

A key mechanistic insight is that Wdr5 reduces the accumulation of "R-loops," which are unstable DNA formations that can lead to DNA damage. Additionally, in the absence of Wdr5, cells fail to activate the DNA damage response (DDR), a critical repair pathway. Restoring DDR-related genes (such as mlh1 and brip1) rescued the defects in HSPCs, underscoring Wdr5's role in coordinating repair mechanisms.

This study is the first to link H3K4 methylation to genome stability in HSPCs. The findings enhance our understanding of HSPC development and may inspire new strategies for regenerative medicine and treatments for blood disorders.

Schematic Diagram depicting the role of Wdr5-mediated H3K4 methylation in HSPC development (Image by Prof. LIU's group)