SETD5 modulates homeostasis of hematopoietic stem cells by mediating RNA Polymerase II pausing in cooperation with HCF-1.

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

Leukemia 2022 Apr

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SETD5 mutations were identified as the genetic causes of neurodevelopmental disorders. While the whole-body knockout of Setd5 in mice leads to embryonic lethality, the role of SETD5 in adult stem cell remains unexplored. Here, a critical role of Setd5 in hematopoietic stem cells (HSCs) is identified. Specific deletion of Setd5 in 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 of Setd5-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. © 2021. The Author(s).

Citation

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. SETD5 modulates homeostasis of hematopoietic stem cells by mediating RNA Polymerase II pausing in cooperation with HCF-1. Leukemia. 2022 Apr;36(4):1111-1122