Setd2-Mediated Epigenetic Regulation Of Erythropoiesis And Hsc Maintenance In Mouse Models

SET domain containing 2 (SETD2) is a methyltransferase for histone 3 lysine 36 tri-methylation (H3K36me3). Using a conditional knockout allele (Setd2Δ/Δ), we recently demonstrated that their SLAM-hematopoietic stem cells (SLAM-HSCs) have intrinsic defects in maintaining quiescence and multi-lineage differentiation potential. Setd2Δ/Δ mice show decreased lymphoid and myeloid progenitors except increased pre-colony-forming-unit-erythroid (Pre CFU-E) and erythroblasts in bone marrow (BM); they suffer from lethal macrocytic anemia. A decreasing H3K36me3, but increasing H3K36me1 and H3K36me2, were observed in Setd2Δ/Δ mice. As a consequence, RNA polymerase II elongation is enhanced at a subset of genes, including Myc which encodes a transcriptional factor essential for erythropoiesis and HSC activation (Zhou Y., Haematologica, 2018). In the current study, we aim to investigate the detailed mechanisms of Setd2 deficiency in the intrinsic and extrinsic mechanisms of erythropoiesis and in the maintenance of HSC from definitive HSCs to adult.