Phosphorylation state of the histone variant H2A.X controls human stem and progenitor cell fate decisions

Stem cell fate decisions are tightly regulated by several processes, including epigenetic based histone modifications. Histone variants (HVs) represent a subfamily of epigenetic regulators implicated in early embryonic development, but their role in stem cell fate control has not been targeted. Here we reveal direct involvement of phosphorylation state of the histone variant H2A.X that allows control of self-renewal and differentiation of human pluripotent stem cells (hPSCs) and leukemic patient derived progenitors. Reduced levels of γH2A.X using either genetic approaches or chemical targeting allowed enhanced hPSC differentiation toward the mesodermal (hematopoietic) lineage with concomitant inhibition of ectodermal (neural) development. In contrast, activation and sustained levels of phosphorylated H2A.X enhanced hPSC ectodermal fate while suppressing mesodermal derived hematopoiesis. This controlled bifurcation of neural vs. hematopoietic differentiation correlated to occupancy of γH2A.X at gene loci associated with lineage selection. Drug modulation of H2A.X phosphorylation was extended to somatic cells to reveal the ability to induce differentiation of leukemic progenitors and serve as a biomarker in a cohort of adult leukemic patients. Our study uncovers a mechanism of cell-fate control of hPSCs extended to neoplastic progenitors through a histone variant epigenetic regulation