生物
造血
细胞生物学
干细胞
DNA复制
祖细胞
DNA损伤
表观遗传学
细胞周期
细胞
遗传学
DNA
基因
作者
Jodi Lynch,Estelle Troadec,Tsz Kan Fung,Kornelia Gladysz,Clémence Virely,Priscilla Nga Ieng Lau,Nicole W. T. Cheung,Bernd B. Zeisig,Jason Wong,Massimo Lopes,Suming Huang,Chi Wai Eric So
出处
期刊:Blood
[American Society of Hematology]
日期:2024-01-11
标识
DOI:10.1182/blood.2023022082
摘要
Maintenance of quiescence and DNA replication dynamics are two paradoxical requirements for the distinct states of dormant and active hematopoietic stem cells (HSCs), which are required to preserve the stem cell reservoir and replenish the blood cell system in response to hematopoietic stress respectively. Here, we show that key self-renewal factors, β-catenin or Hoxa9, largely dispensable for HSC integrity in fact have dual functions in maintaining quiescence and enabling efficient DNA replication fork dynamics to preserve the functionality of hematopoietic stem and progenitor cells (HSPCs). While β-catenin or Hoxa9 single knockout (KO) exhibited mostly normal hematopoiesis, their co-inactivation led to severe hematopoietic defects stemmed from aberrant cell cycle, DNA replication and damage in HSPCs. Mechanistically, β-catenin and Hoxa9 function in a compensatory manner to sustain key transcriptional programs that converge on the pivotal downstream target and epigenetic modifying enzyme, Prmt1, which protects the quiescent state and ensures an adequate supply of DNA replication and repair factors to maintain robust replication fork dynamics. Inactivation of Prmt1 phenocopied both cellular and molecular phenotypes of β-catenin/Hoxa9 combined KO, which at the same time could also be partially rescued by Prmt1 expression. The discovery of the highly resilient β-catenin/Hoxa9/Prmt1 axis in protecting both quiescence and DNA replication dynamics essential for HSCs at different key states provides not only novel mechanistic insights into their intricate regulation but also a potential tractable target for therapeutic intervention.
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