<i>Setd2</i> regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation

Abstract

<i>SET domain containing 2</i> (<i>Setd2</i>), encoding a histone methyltransferase, is associated with many hematopoietic diseases when mutated. By generating a novel exon 6 conditional knockout mouse model, we describe an essential role of <i>Setd2</i> in maintaining the adult hematopoietic stem cells. Loss of <i>Setd2</i> results in leukopenia, anemia, and increased platelets accompanied by hypocellularity, erythroid dysplasia, and mild fibrosis in bone marrow. <i>Setd2</i> knockout mice show significantly decreased hematopoietic stem and progenitor cells except for erythroid progenitors. <i>Setd2</i> knockout hematopoietic stem cells fail to establish long-term bone marrow reconstitution after transplantation because of the loss of quiescence, increased apoptosis, and reduced multiple-lineage terminal differentiation potential. Bioinformatic analysis revealed that the hematopoietic stem cells exit from quiescence and commit to differentiation, which lead to hematopoietic stem cell exhaustion. Mechanistically, we attribute an important <i>Setd2</i> function in murine adult hematopoietic stem cells to the inhibition of the Nsd1/2/3 transcriptional complex, which recruits super elongation complex and controls RNA polymerase II elongation on a subset of target genes, including <i>Myc</i> Our results reveal a critical role of <i>Setd2</i> in regulating quiescence and differentiation of hematopoietic stem cells through restricting the NSDs/SEC mediated RNA polymerase II elongation.