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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.

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