1342 Polycomb Repressive Complex 2 Controls Differentiation Program in Human Epidermal Progenitor Cells

Polycomb repressive complex 2 (PRC2) catalyses methylation of Lys-27 of histone H3 leading to transcriptional repression of target genes. In mouse skin, Ezh2, a catalytic subunit of PRC2, prevents premature differentiation of epidermal progenitor cells and their ectopic differentiation into Merkel cells. However, the role of PRC2 in human skin homeostasis remains unclear. Here, we show an increased EZH2 and H2K27me3 expression in differentiated suprabasal keratinocytes in human epidermis. Similarly, Ca2+-induced differentiation markedly up-regulated EZH2 expression in primary human epidermal keratinocytes (NHEK). Interestingly, knockdown of PRC2 subunits EZH1, EZH2 and EED using siRNA and small molecule inhibitors GSK126 and UNC1999 up-regulated expression of KRT1, LOR and FLG genes and suppressed cell proliferation in NHEKs cultured in low Ca2+ condition. However, disruption of the PRC2 function in already differentiated keratinocytes did not affect expression of the terminal differentiation genes. Bioinformatic analysis of genome-wide EZH2 and H3K27me3 distribution identified distinct sets of PRC2 targets in undifferentiated progenitor cells and their differentiated progeny. Taken together, these results highlight a critical role for PRC2 in human epithelial progenitor cells proliferation and differentiation.