Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis
A recent Nucleic Acids Research paper by Svitlana Kurinna and the Werner group demonstrates a physical interaction of the p63 and NRF2 transcription factors, which controls proliferation of keratinocytes.
The epidermis of human skin provides an essential barrier to the environment. This barrier is established when keratinocytes proliferate in deep layers of the epidermis, differentiate, and move towards the surface. Understanding the mechanisms, which regulate normal proliferation of keratinocytes, and development of strategies to further promote their proliferation, is of a high value to patients suffering from impaired wound healing or various other skin diseases.
Researchers at IMHS identified a previously uncharacterized mechanism that regulates growth and differentiation of keratinocytes. Two transcription factors, NRF2 and p63, were found to interact on regulatory sequences of the DNA during keratinocyte proliferation and differentiation. NRF2 occupies both the promoters and enhancers of its target genes in normal skin and when activated, shifts the occupancy towards the promoters. p63, a master regulator of epidermal development, interacts with enhancers and promoters occupied by activated NRF2. NRF2 and p63 together enhance expression of several genes involved in keratinocyte proliferation or differentiation. One of them encodes CDK12, which was identified as a novel regulator of keratinocyte proliferation. The NRF2-p63 interaction is significantly promoted by activation of NRF2, suggesting pharmacological activation of this transcription factor as a way to enhance proliferation of keratinocytes and improve repair of human skin.
First author Svitlana Kurinna was a postdoc in the Werner lab and is now group leader in Manchester.
Link to the paper in external page Nucleic Acids Research.