Abstract
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.
Highlights
Stem cells maintain their self-renewal and differentiation through tight regulation of gene expression patterns at the transcriptional and epigenetic levels
We observed modest decreased frequencies of B and T lymphocytes in the peripheral blood (PB) and bone marrow (BM) and a significant increased frequency of granulocytes/monocytes in PB of Setd5CKO mice when compared with the control animals (Fig. 1A, Figure S1I)
In this study, we investigated the roles of Setd5 in hematopoietic stem cells (HSCs) during hematopoiesis
Summary
Stem cells maintain their self-renewal and differentiation through tight regulation of gene expression patterns at the transcriptional and epigenetic levels. De novo mutations in the Setd gene have been identified as the genetic causes of intellectual disability and autism spectrum disorders [8,9,10,11]. SETD5 was identified as a key mediator of pancreatic cancer resistance to MEK1/2 inhibition targeted therapy [7], suggesting that its physiological and pathological roles might be diverse and tissue or cell type specific. The number of CD41+ early hematopoietic cells declined in the blood island of Setd homozygous knockout mice [5]. These data suggested a potential role of SETD5 in hematopoiesis
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