Key changes in chromatin mark mammalian epidermal differentiation and ageing

Abstract

ABSTRACT Dynamic shifts in chromatin states occur during embryonic epidermal development to support diverse epigenetic pathways that regulate skin formation and differentiation. However, it is not known whether the epigenomes established during embryonic development are maintained into adulthood or how these epigenetic mechanisms may be altered upon physiological ageing of the tissue. Here, we systematically profiled the nuclear enrichment of five key histone modifications in young and aged mouse epidermis and identified distinct chromatin states that are tightly correlated with cellular differentiation, as well as chromatin alterations that accompanied epidermal ageing. Our data showed that histone modifications, which become differentially enriched in undifferentiated basal or differentiated suprabasal cells during embryonic development, retained their distinct cell-type specific enrichment patterns in both young and aged adult tissues. Specifically, high levels of H3K4me3, H4K20me1 and H4K16ac marked the proliferative basal cells, while differentiated suprabasal cells accumulated H3K27me3 and H4K20me3 heterochromatin with a concomitant deacetylation of H4K16. We further identified shifts in the chromatin in the aged basal epidermis, which exhibited markedly reduced levels of H4K16ac, absence of high H4K20me1 staining and increased cell-to-cell variability in total histone H3 and H4 content. Changes in the chromatin profiles in aged tissues paralleled the altered expression of their corresponding histone modifiers in the basal keratinocytes. These results thus reveal the key histone signatures of epidermal differentiation that are conserved from embryonic development to adult homoeostasis, and provide insights into the epigenetic pathways underlying physiological skin ageing.