Divergent functions of histone acetyltransferases KAT2A and KAT2B in keratinocyte self-renewal and differentiation.

The mammalian epidermis undergoes constant renewal, replenished by a pool of stem cells and terminal differentiation of their progeny. This is accompanied by changes in gene expression and morphology that are orchestrated, in part, by epigenetic modifiers. Here, we define the role of the histone acetyltransferase KAT2A in epidermal homeostasis and provide a comparative analysis that reveals key functional divergence with its paralog KAT2B. In contrast to the reported function of KAT2B in epidermal differentiation, KAT2A supports the undifferentiated state in keratinocytes. RNA-seq analysis of KAT2A- and KAT2B- depleted keratinocytes revealed dysregulated epidermal differentiation. Depletion of KAT2A led to premature expression of epidermal differentiation genes in the absence of inductive signals, whereas loss of KAT2B delayed differentiation. KAT2A acetyltransferase activity was indispensable in regulating epidermal differentiation gene expression. The metazoan-specific N terminus of KAT2A was also required to support its function in keratinocytes. We further showed that the interplay between KAT2A- and KAT2B-mediated regulation was important for normal cutaneous wound healing in vivo. Overall, these findings reveal a distinct mechanism in which keratinocytes use a pair of highly homologous histone acetyltransferases to support divergent functions in self-renewal and differentiation processes.

Key changes in chromatin mark mammalian epidermal differentiation and ageing.

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.