Treatment with lysine deacetylase inhibitors (KDACi) for haematological malignancies, is accompanied by haematological side effects including thrombocytopenia, suggesting that modulation of protein acetylation affects normal myeloid development, and specifically megakaryocyte development. However, the effects of KDACi inhibitors on human hematopoiesis have not been systematically investigated. In this study by Marije Bartels and Anita Govers, utilising ex-vivo differentiation of human haematopoietic progenitor cells, we investigated the effects of two functionally distinct KDACi, valproic acid (VPA), and nicotinamide (NAM), on megakaryocyte differentiation, and lineage choice decisions. While both being KDACi, VPA and NAM can differentially regulate cell fate decisions during megakaryocyte, and erythroid (ME) development through specific effects on promoter-acetylation of genes regulating ME-lineage development. Here, we compared the effects of VPA treatment with NAM treatment on human ME-lineage development, and further progression into the megakaryocytic lineage. Our data demonstrate for the first time that KDAC and SIRT inhibition differentially modulates the expansion and differentiation of ME-progenitors (MEP). Utilising a histone 3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation- (ChIP) sequencing approach, we identified key regulatory genes implicated in myeloid progenitor function, and ME-lineage differentiation, directly regulated by VPA and NAM treatment. These findings increase our understanding of the effects of KDACi on normal haematopoiesis which should be considered when using KDACi in a clinical context. This work has recently been accepted for publication in PLoS ONE.