Abstract
Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2 and p63- a key player in epithelial morphogenesis. Chromatin immunoprecipitation combined with sequencing and reporter assays identifies enhancers and promoters that are simultaneously activated by NRF2 and p63 in human keratinocytes. Modeling of p63 and NRF2 binding to nucleosomal DNA suggests their chromatin-assisted interaction. Pharmacological and genetic activation of NRF2 increases NRF2–p63 binding to enhancers and promotes keratinocyte proliferation, which involves the common NRF2–p63 target cyclin-dependent kinase 12. These results unravel a collaborative function of NRF2 and p63 in the control of epidermal renewal and suggest their combined activation as a strategy to promote repair of human skin and other stratified epithelia.
Highlights
The development and regeneration of epithelial tissues is a highly organized process, which is at least in part regulated at the level of transcription [1]
PNRF2+p63+Ki67+ keratinocytes significantly increased in total numbers in KEAP1 KO cells in the presence or absence of growth factors (Figure 6G and H). While these results demonstrate that NRF2 activation promotes keratinocyte proliferation, knockdown of NRF2 alone and reduction of its basal activity had no effect on proliferation in 2D and under exponential growth conditions (Figure 6I)
We discovered a physical interaction of two key regulators of epithelial function: p63 and NRF2
Summary
The development and regeneration of epithelial tissues is a highly organized process, which is at least in part regulated at the level of transcription [1]. Further activation of NRF2 occurs through conformational changes of KEAP1, which are mainly induced by the covalent coupling of electrophilic molecules to this protein These changes result in the weakening of the NRF2–KEAP1 interaction and stabilization of NRF2. The loss of Nrf inhibited the mobilization of p63-positive stem cells in the lung, a key event for the repair of this tissue and prevention of fibrosis [12]. These studies suggest that both Nrf and p63 are important for epithelial cell proliferation and/or differentiation, but a potential functional interaction of p63 and NRF2 has as yet not been demonstrated. The combined activity of NRF2 and p63 is functionally relevant, since it promotes keratinocyte proliferation and the regenerative potential of the skin
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