Cell proliferation is essential to rapid tissue growth and repair, but can result in replication‐associated genome damage. Here, we implicate the transcription factor Gata6 in adult mouse hair follicle regeneration where it controls the renewal of 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 in vivo Gata6 stimulates EDA‐receptor signaling adaptor Edaradd level and NF‐κB pathway activation, known to be important for DNA damage repair and stress response in general and for hair follicle growth in particular. In cultured keratinocytes, Edaradd rescues DNA damage, cell survival, and proliferation of Gata6 knockout cells and restores MCM10 expression. 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 at key stages of rapid tissue growth. Our data may add to understanding why Gata6 is a frequent target of amplification in cancers.
The developmental transcription factor Gata6 functions in adult hair follicle regeneration by controlling survival of proliferating epithelial precursor cells. Gata6 protects from DNA damage and acts as rheostat for differentiation, partly by governing expression of morphogenetic EDA‐signaling adaptor Edaradd and NF‐κB activation.
Gata6 functions in ectoderm‐derived tissue and plays a role in genome maintenance in proliferative cells.
Gata6 controls the hair follicle cycle through matrix cell formation and survival.
Developmental transcription factors prevent replication‐associated DNA damage during rapid tissue growth.
Gata6 is required upstream of Edaradd expression and NF‐κB activation.
- Received April 16, 2016.
- Revision received September 30, 2016.
- Accepted October 28, 2016.
- © 2016 The Authors