Wdr5-mediated H3K4 methylation facilitates HSPC development via maintenance of genomic stability in zebrafish

• 成果类型: Article
• 署名作者: Wang, Xiaohan; Liu, Mengyao; Zhang, Yifan; Ma, Dongyuan; Wang, Lu; Liu, Feng
• 署名单位: Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Beijing Institute for Stem Cell & Regenerative Medicine; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Institute of Hematology & Blood Diseases Hospital - CAMS; Shandong University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13371
• DOI: 10.1073/pnas.2420534122
• 发表日期: 2025-03-25
• 关键词: regulates hematopoietic stem; dna-damage response; vascular niche; r-loops; replication; expansion; conflicts

摘要

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 wdr5 led to a severe reduction of HSPC pool in the caudal hematopoietic tissue, accompanied with attenuated H3K4 methylation level and evidentp53-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, mutt homolog 1 and breast and ovarian cancer interacting helicase 1, 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.