Gata6 promotes hair follicle matrix progenitor cell renewal by genome maintenance via Edaradd/NF-?B

Cell proliferation is essential to rapid tissue growth and repair, but is inherently associated with considerable genome damage that cells must efficiently prevent or fix to prevent cell cycle arrest. Here, we implicate the transcription factor Gata6 in regulation of adult mouse hair follicle regeneration where it controls the renewal of the rapidly proliferating epithelial (matrix) progenitors and hence the extent of production of terminally differentiated lineages. We find that Gata6 protects against DNA damage associated with proliferation, thus preventing cell cycle arrest and apoptosis. Furthermore, we show that Gata6 stimulates the Eddarad/NF-kB pathway, important for DNA-damage repair and stress response in general, and for hair follicle growth in particular. Finally, we find Edaradd essential, downstream of Gata6 for cell survival and proliferation. Our data add to recent evidence in embryonic stem and neural progenitor cells, suggesting a model whereby developmentally regulated transcription factors protect from DNA damage associated with proliferation occurring at key stages of rapid tissue growth. Our data may aid in understanding why Gata6 is a frequent target of amplification in cancers. Overall design: Gene expression profiling by mRNA-seq to identify differentially expressed genes in wild type (WT) and Gata6 induced knockout (iKO) mouse epidermal keratinocytes

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Wang AB, Zhang YV, Tumbar T