A research team led by Prof. LIU Feng from the Institute of Zoology of the Chinese Academy of Sciences has uncovered a critical mechanism by which the Wdr5 ensures the survival and genomic stability of hematopoietic stem and progenitor cells (HSPCs) during embryonic development.

HSPCs, the “seed cells” of the blood system, originate in the aorta-gonad-mesonephros region during early embryonic development. They later migrate to the caudal hematopoietic tissue (similar to the fetal liver in mammals) to multiply rapidly. However, this fast-paced growth comes with risks: DNA replication stress can destabilize the genome, leading to DNA damages or even cell death. Maintaining genomic stability is thus a critical challenge for these cells.

On March 20, 2025, a study led by Prof. Feng Liu, published in PNAS, revealed that Wdr5-dependent H3K4 methylation promotes HSPC development by suppressing aberrant R-loop accumulation and activating the DNA damage response (DDR) pathway to safeguard genomic stability.

Using zebrafish as a model, the team discovered that Wdr5 acts as a genomic guardian by regulating a specific epigenetic mark—H3K4 methylation. When Wdr5 was disabled, HSPC numbers dropped sharply, accompanied by widespread DNA damage and cell death. The study revealed two key mechanisms:

1. Blocking Harmful DNA Structures: Wdr5 reduces the buildup of “R-loops,” unstable DNA formations that trigger DNA damage.

2. Activating Repair Systems: Without Wdr5, cells fail to activate the DNA damage response (DDR), a critical repair pathway. Restoring DDR-related genes (e.g., mlh1 and brip1) rescued HSPC defects, highlighting Wdr5’s role in coordinating repair.

This study is the first to link H3K4 methylation to genome stability in HSPCs. “Wdr5 acts like a ‘genome security guard,’ ensuring these cells development safely even under stress,” explained Professor Liu. The findings deepen 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 credit: Prof. LIU's group)