SRA

The correct balance between self-renewal and differentiation of hematopoietic stem cells (HSC) is orchestrated by the crosstalk between extrinsic and intrinsic factors. A combination of transcriptional regulators and chromatin-based epigenetic changes provide a fine-tuning mechanism to determine HSC fate. We report that the histone H4 lysine 16 (H4K16) specific lysine acetyl-transferase MOF (KAT8) shows dynamic chromatin occupancy during HSC differentiation. MOF regulates erythroid commitment by regulating the expression of key haematopoietic genes. Indeed, loss of just one copy of Mof perturbs HSC commitment, leading to skewed granulocytic lineage commitment and impaired erythroid maturation in mice. Wild-type MOF and strikingly, enforced expression of the transcription factor GATA-1, rescued hematopoietic skewing of this granulocytic fate bias. Furthermore, single-cell RNA-seq of Mof haploinsufficient HSCs revealed an enrichment of a novel immature heterogeneous sub-population of cells with increased proliferation potential, indicative of an enhanced pro-leukemic state. Therefore, our results demonstrate an unprecedented role of MOF in the regulation of HSC plasticity, identity and differentiation. Overall design: 15 cells from 6 different progenitor cells: HSCs (LSK+CD34-Flt3-CD48-CD150+), MPP2 (LSK+CD34+Flt3-CD48+CD150+), MPP3 (LSK+CD34+Flt3-CD48+CD150-), MPP4 LSK+CD34+Flt3+CD48+CD150-), CMP Lin-Sca-1-cKit+CD34+IL7r-CD16/32low) and MEP (Linegae-Sca-1-cKit+CD34-IL7r-CD16/32-) were sorted by Aria FACS Fusion II (BD)