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102 EZH2 is required for human hair follicle growth and epidermal differentiation

      Enhancer of zeste homolog 2 (Ezh2) is a catalytic subunit of the polycomb repressive complex 2 which methylates ‘Lys-27’ of histone H3 leading to transcriptional repression of target genes. Ezh2 functions as a critical regulator of stem cell identity and their differentiation in embryonic and adult tissues. In mouse skin, Ezh2 prevents premature differentiation of epidermal progenitor cells, and is required for proliferative activity of hair follicle stem cells. The role of EZH2 in human skin homeostasis remains unclear. Here, we show that in human skin Ezh2 is predominantly expressed in the epithelial cells. In the epidermis, its expression is increased in differentiating cells of the suprabasal layer. Indeed, Ezh2 expression is markedly up-regulated in Ca2+-induced differentiation in primary human keratinocytes. In anagen hair follicles, Ezh2 is expressed in Keratin15/Keratin 19/CD34-positive progenitor cells in the outer root sheath, as well as in differentiating cells of the inner root sheath and precortex, whilst no Ezh2 expression was detected in the dermal papilla and connective tissue sheath. Interestingly, EZH2 knockdown using siRNA together with a small molecule inhibitor GSK126 up-regulated expression of KER1 and LOR genes in primary human keratinocytes. Inhibition of Ezh2 with a selective small molecule, 3-Deazaneplanocin A, caused a dose-dependent retardation of hair growth ex vivo. The latter was associated with decreased proliferation and increased apoptosis in the outer root sheath. These results suggest that Ezh2 plays a critical role in the control of human epithelial progenitor cells proliferation and differentiation.