H3K9 methyltransferase Setdb1 is a critical regulator of hematopoietic stem and progenitor cells.

Setdb1, an H3K9 histone methyltransferase, plays an essential role in silencing of endogenous retroviral elements (ERVs) in early embryo and embryonic stem cells (ESCs). However, its role in somatic stem cells remains unclear. We show that deletion of Setdb1 causes rapid depletion of hematopoietic stem and progenitor cells (HSPCs) and leukemic stem cells. Contrary to ESCs, ERVs were largely repressed and stem cell gene signature was maintained in Setdb1-deficient HSPCs. Instead, a list of non-hematopoietic genes were ectopically activated following reduction in H3K9me3 levels, including epithelial cell adhesion molecule (EpCAM) and Fructose-1,6-bisphosphatase (Fbp2), a muscle-specific gluconeogenesis enzyme gene, in HSPCs, resulting in egression of HSPCs from the bone marrow and compromised cell growth and energy production. Our findings demonstrate that Setdb1 little contributes to the silencing of ERVs in HSPCs but is critical for restricting ectopic activation of non-hematopoietic genes detrimental to HSPCs.

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