HMN 2025: How Zebrafish analysis highlights protein Wdr5’s function in stopping blood cell DNA harm

A research led by Prof. Liu Feng from the Institute of Zoology of the Chinese Academy of Sciences has recognized a vital function for the tryptophan-aspartic acid (WD) repeat protein 5 (Wdr5) in sustaining the survival and genomic integrity of hematopoietic stem and progenitor cells (HSPCs) throughout embryonic growth. The findings had been published within the Proceedings of the National Academy of Sciences.

HSPCs are the foundational “seed cells” of the blood system. They emerge within the aorta-gonad-mesonephros area throughout early embryogenesis and subsequently migrate to the caudal hematopoietic tissue, which is akin to the mammalian fetal liver. In this location, they bear fast proliferation. However, this intense replication part makes HSPCs prone to DNA harm and genomic instability.

In this study, utilizing zebrafish as a model organism, the researchers found that Wdr5 capabilities as a genomic guardian by regulating a selected epigenetic mark—H3K4 methylation. When Wdr5 was disabled, the variety of HSPCs dropped considerably, resulting in widespread DNA harm and cell dying.

A key mechanistic perception is that Wdr5 reduces the buildup of “R-loops,” that are unstable DNA formations that may result in DNA harm. Additionally, within the absence of Wdr5, cells fail to activate the DNA harm response (DDR), a crucial restore pathway. Restoring DDR-related genes (akin to mlh1 and brip1) rescued the defects in HSPCs, underscoring Wdr5’s function in coordinating restore mechanisms.

This study is the primary to hyperlink H3K4 methylation to genome stability in HSPCs. The findings improve our understanding of HSPC growth and should encourage new methods for regenerative medication and coverings for blood issues.