title: Gata6 promotes hair follicle progenitor cell renewal by genome maintenance during proliferation.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
authors.forename: Ying V
authors.initials: YV
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA tt252@cornell.edu.
authors.forename: Tudorita
authors.identifier: 0000-0002-2273-1889
authors.initials: T
authors.lastname: Tumbar
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D004260:DNA Repair; D053362:Edar-Associated Death Domain Protein / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000378:metabolism*; D018859:Hair Follicle / Q000166:cytology*; D051379:Mice; D064110:Minichromosome Maintenance Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*
chemical_list: D053362:Edar-Associated Death Domain Protein; C506124:Edaradd protein, mouse; D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; C562158:MCM10 protein, mouse; D016328:NF-kappa B; D064110:Minichromosome Maintenance Proteins
keywords: DNA damage; Gata6; hair follicle; progenitor matrix cell; replication stress