Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis

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...

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Published in:Nucleic acids research 2021-04, Vol.49 (7), p.3748-3763
Main Authors: Kurinna, Svitlana, Seltmann, Kristin, Bachmann, Andreas L, Schwendimann, Andreas, Thiagarajan, Lalitha, Hennig, Paulina, Beer, Hans-Dietmar, Mollo, Maria Rosaria, Missero, Caterina, Werner, Sabine
Format: Article
Language:English
Subjects:
Animals
Cell Proliferation
Cells, Cultured
Cyclin-Dependent Kinases - metabolism
Data Resources and Analyses
Humans
Keratinocytes - cytology
Keratinocytes - metabolism
Mice
NF-E2-Related Factor 2 - physiology
Skin - cytology
Skin - metabolism
Transcription Factors - physiology
Tumor Suppressor Proteins - physiology
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkab167