Wang Xiaohan, Liu Mengyao, Zhang Yifan, Ma Dongyuan, Wang Lu, Liu Feng
State Key Laboratory of Organ Regeneration and Reconstruction, Beijing Institute for Stem Cell and Regenerative Medicine, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Proc Natl Acad Sci U S A. 2025 Mar 25;122(12):e2420534122. doi: 10.1073/pnas.2420534122. Epub 2025 Mar 20.
During fetal stage, hematopoietic stem and progenitor cells (HSPCs) undergo rapid proliferation with a tight control of genomic stability. Although histone H3 lysine 4 (H3K4) methylation has been reported to stabilize the genome in proliferating cells, its specific role in HSPC development remains elusive. In this study, we demonstrated that tryptophan-aspartic acid (WD) repeat protein 5 (Wdr5)-mediated H3K4 methylation is crucial for maintaining genomic stability of proliferating HSPCs in zebrafish embryos. Loss of led to a severe reduction of HSPC pool in the caudal hematopoietic tissue, accompanied with attenuated H3K4 methylation level and evident -dependent apoptosis in the HSPCs. Mechanistically, Wdr5-mediated H3K4 methylation maintains genomic stability by inhibiting the formation of abnormal R-loops in the HSPCs, whereas accumulation of R-loops exacerbates DNA damage. Moreover, the absence of H3K4 trimethylation leads to an inactivated DNA damage response (DDR) pathway, which is deleterious to DNA damage repair and genomic stability. Subsequently, we found that DDR-associated genes, and , are important to ensure HSPC survival, likely by stabilizing their genome. In summary, these findings reveal that Wdr5-mediated H3K4 methylation is essential for HSPC development through tight control of R-loop accumulation and DDR-associated program to ensure genomic stability and survival of proliferating HSPCs.
在胎儿阶段，造血干细胞和祖细胞（HSPCs）经历快速增殖，同时基因组稳定性受到严格控制。尽管有报道称组蛋白H3赖氨酸4（H3K4）甲基化可在增殖细胞中稳定基因组，但其在HSPC发育中的具体作用仍不清楚。在本研究中，我们证明色氨酸-天冬氨酸（WD）重复蛋白5（Wdr5）介导的H3K4甲基化对于维持斑马鱼胚胎中增殖HSPCs的基因组稳定性至关重要。Wdr5缺失导致尾部造血组织中HSPC库严重减少，同时伴随着H3K4甲基化水平降低以及HSPCs中明显的Wdr5依赖性细胞凋亡。机制上，Wdr5介导的H3K4甲基化通过抑制HSPCs中异常R环的形成来维持基因组稳定性，而R环的积累会加剧DNA损伤。此外，H3K4三甲基化的缺失会导致DNA损伤反应（DDR）途径失活，这对DNA损伤修复和基因组稳定性有害。随后，我们发现DDR相关基因[具体基因未给出]对于确保HSPC存活很重要，可能是通过稳定它们的基因组来实现。总之，这些发现揭示了Wdr5介导的H3K4甲基化对于HSPC发育至关重要，它通过严格控制R环积累和DDR相关程序来确保增殖HSPCs的基因组稳定性和存活。
