Authors: Mengke Li, Chen Qiu, Yujie Bian, Deyang Shi, Bichen Wang, Qiuyi Ma, Xiaomin Wang, Jun Shi, Lianfeng Zhang, Yuanwu Ma, Ping Zhu, Tao Cheng, Yajing Chu, Weiping Yuan
Published: 2021-12-01
DOI: 10.1038/s41375-021-01481-1
Source: Full article
AbstractSETD5mutations were identified as the genetic causes of neurodevelopmental disorders. While the whole-body knockout ofSetd5in mice leads to embryonic lethality, the role of SETD5 in adult stem cell remains unexplored. Here, a critical role ofSetd5in hematopoietic stem cells (HSCs) is identified. Specific deletion ofSetd5in hematopoietic system significantly increased the number of immunophenotypic HSCs by promoting HSC proliferation.Setd5-deficient HSCs exhibited impaired long-term self-renewal capacity and multiple-lineage differentiation potentials under transplantation pressure. Transcriptome analysis ofSetd5-deficient HSCs revealed a disruption of quiescence state of long-term HSCs, a cause of the exhaustion of functional HSCs. Mechanistically, SETD5 was shown to regulate HSC quiescence by mediating the release of promoter-proximal paused RNA polymerase II (Pol II) on E2F targets in cooperation with HCF-1 and PAF1 complex. Taken together, these findings reveal an essential role of SETD5 in regulating Pol II pausing-mediated maintenance of adult stem cells.