Age-related increase of EED expression in early hematopoietic progenitor cells is associated with global increase of the histone modification H3K27me3.

Human hematopoietic stem and progenitor cells (HSPCs) from umbilical cord blood exhibit higher differentiation potential and repopulation capacity compared to adult HSPCs. The molecular basis for these functional differences is currently unknown. Upon screening for epigenetic effector genes being differentially expressed in neonatal and adult HSPC subpopulations, the Polycomb Repressive Complex 2 (PRC2) member EED was identified. Even though EED is expressed at comparable amounts in neonatal and adult multipotent HSPCs, early adult lineage committed progenitors of the lymphomyeloid (LM) and erythromyeloid lineages expressed higher EED amounts than neonatal HPCs. We demonstrate that EED overexpression directly leads to higher H3K27me3 levels, a repressive histone modification that is mediated by the PRC2 complex. Quantitative analysis of H3K27me3 levels by FPLC-based ELISA revealed elevated levels in primary blood cells from adults. Besides quantitative changes, gene ontology analysis of the genome-wide H3K27me3 distribution revealed qualitative changes in adult HSPCs with elevated levels in genes associated with nonhematopoietic development pathways. In contrast, H3K4me3 which labels active chromatin was enriched on hematopoietic genes. In vitro differentiation of EED-transfected neonatal HSPCs revealed aberrant expression of the myelopoietic marker CD14, suggesting that EED affects the lymphoid versus myeloid decision processes within the lymphomyeloid lineage. This is in line with LM progenitors having the most pronounced differences in EED expression. Highlighting the dynamic roles of epigenetic modifications in human hematopoiesis, the present data demonstrate shifts in the PRC2-associated histone modification H3K27me3 from birth to adulthood.