The H3K4 methyltransferase Setd1b is essential for hematopoietic stem and progenitor cell homeostasis in mice

Abstract

Hematopoietic stem cells require MLL1, which is one of six Set1/Trithorax-type histone 3 lysine 4 (H3K4) methyltransferases in mammals and clinically the most important leukemia gene. Here, we add to emerging evidence that all six H3K4 methyltransferases play essential roles in the hematopoietic system by showing that conditional mutagenesis of Setd1b in adult mice provoked aberrant homeostasis of hematopoietic stem and progenitor cells (HSPCs). Using both ubiquitous and hematopoietic-specific deletion strategies, the loss of Setd1b resulted in peripheral thrombo- and lymphocytopenia, multilineage dysplasia, myeloid-biased extramedullary hematopoiesis in the spleen, and lethality. By transplantation experiments and expression profiling, we determined that Setd1b is autonomously required in the hematopoietic lineages where it regulates key lineage specification components, including Cebpa, Gata1, and Klf1. Altogether, these data imply that the Set1/Trithorax-type epigenetic machinery sustains different aspects of hematopoiesis and constitutes a second framework additional to the transcription factor hierarchy of hematopoietic homeostasis.

SET domain containing 1B gene is mutated in primary hepatic neuroendocrine tumors

“…SETD1B is a maternal effect gene required for the oogenic gene expression program and a novel recurrently mutated gene in chronic myeloid leukemia . SETD1B is essential for hematopoietic stem and progenitor cell homeostasis in adult mice . De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism .…”

MLL1 promotes myogenesis by epigenetically regulating Myf5

“…In vertebrates, post‐translational modifications of histones, such as methylation, phosphorylation and acetylation, are extensively used to ensure the temporal and spatial expressions of key genes during tissue‐specific differentiation and development . Lysine methylation on histone 3 (H3) is an important part of the epigenetic regulation network and integrates both cooperative and antagonistic modifications .…”

The MLL/SET family and haematopoiesis

“…More recently, detailed analyses have demonstrated the impact of Setd1a and Setd1b deletion on HSPCs during foetal and adult haematopoiesis [ 111 , 112 ]. Vav-Cre-mediated Setd1a loss during foetal development leads to death 7 to 20 days post-birth from a significantly depleted LSK compartment, which must have failed to establish because of Setd1a deficiency in the first definitive HSCs that did not form or expand sufficiently [ 111 ].…”

“…Both studies showed that Mll1 does not affect Hoxb4 expression, which may underlie the difference in ESC fate induction. In contrast, to the phenotype for Setd1a deletion, Vav-Cre-specific Setd1b −/− null mice survive to a median of 25 weeks, suggesting that it is dispensable for the specification of a foetal haematopoietic system [ 112 ]. However, Setd1b −/− null foetal HSPCs were not tested in any functional assays.…”

“…Transplantations of cells derived from both Setd1b knockout systems massively expanded the MPP compartment in the bone marrow, likely causing the accumulation of myeloid cells. Competitive transplantation of total bone marrow derived from Setd1b −/− Rosa26-Cre-ERT2 showed no MPP expansion from null cells but the LT-HSC, LMPP, and LK compartments were significantly depleted and, correspondingly in the spleen, B-, T- and myeloid cell contribution from null cells was significantly reduced [ 112 ]. This negated a role for Setd1b in maintaining MPP numbers, and allowed for the demonstration of intrinsic Setd1b function that was masked by compensatory stress-based mechanisms that arise during defective haematopoiesis, imposed by a non-competitive setting.…”