ΔNp63α-mediated epigenetic regulation in keratinocyte senescence

Abstract

Keratinocyte senescence contributes to skin ageing and epidermal dysfunction. According to the existing knowledge, the transcription factor ΔNp63α plays pivotal roles in differentiation and proliferation of keratinocytes. It is traditionally accepted that ΔNp63α exerts its functions via binding to promoter regions to activate or repress gene transcription. However, accumulating evidence demonstrates that ΔNp63α can bind to elements away from promoter regions of its target genes, mediating epigenetic regulation. On the other hand, several epigenetic alterations, including DNA methylation, histone modification and variation, chromatin remodelling, as well as enhancer-promoter looping, are found to be related to cell senescence. To systematically elucidate how ΔNp63α affects keratinocyte senescence via epigenetic regulation, we comprehensively compiled the literatures on the roles of ΔNp63α in keratinocyte senescence, epigenetics in cellular senescence, and the relation between ΔNp63α-mediated epigenetic regulation and keratinocyte senescence. Based on the published data, we conclude that ΔNp63α mediates epigenetic regulation via multiple mechanisms: recruiting epigenetic enzymes to modify DNA or histones, coordinating chromatin remodelling complexes (CRCs) or regulating their expression, and mediating enhancer-promoter looping. Consequently, the expression of genes related to cell cycle is modulated, and proliferation of keratinocytes and renewal of stem cells are maintained, by ΔNp63α. During skin inflammaging, the decline of ΔNp63α may lead to epigenetic dysregulation, resultantly deteriorating keratinocyte senescence.

Keywords: Keratinocyte; cell proliferation; cellular senescence; chromatin remodeling; epigenetic regulation; skin aging; ΔNp63α.

Figure 1.

Pathways through which ΔNp63α regulates keratinocyte senescence and ΔNp63α is regulated. (a) ΔNp63α regulates transcription of diverse genes involved in cell cycle. Consequently, keratinocyte senescence and its detrimental outcomes are prevented. (b) ΔNp63α transactivates multiple genes to activate Hh, Notch, and Wnt signaling pathways. In turn, stem cell self-renewal is maintained. (c) Various stresses can stimulate p38 MAPK or PI3K/Akt pathways, resulting in downregulation of ΔNp63α at the mRNA or protein level.

Figure 2.

Mechanisms of ΔNp63α-mediated epigenetic regulation in preventing keratinocyte senescence. (a) As a traditional transcription factor, ΔNp63α binds to promoter regions, antagonizing its homologues (TAp63, p73 or p53), as well as recruiting other transcription factors (TFs) and RNA polymerase II (RNApol II), regulating genes related to cell cycle and chromatin remodeling complex (CRC). (b) ΔNp63α recruits diverse epigenetic enzymes (e.g., DNMT3A, KMT2D, HDAC1/2), leading to either active or repressive modification of DNA and histones. (c) ΔNp63α cooperates with CTCF or NRF2 to mediate enhancer-promoter looping. (d) ΔNp63α can also recruit CRCs (e.g., BAF, ACTL6A, SRCAP) to change chromatin configurations, which may either increase or decrease DNA accessibility for transcription machinery. Resultantly, proliferative genes are upregulated, while anti-proliferative genes are downregulated. Therefore, proliferation of keratinocytes is maintained and senescence is prevented.