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-jB 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.

Role of bulge epidermal stem cells and TSLP signaling in psoriasis

“…Only bulge HF‐SCs exhibited reduced c‐JUN/JUNB expression, while basal and suprabasal ORS layers in the sub‐bulge and proximal bulb regions maintained the expression of c‐JUN/JUNB (Fig EV1B and C). In addition, other regulators of HF‐SC renewal from other regions in the hair follicle, such as GATA‐6, expressed in progenitor matrix cells (bulb) in mice were analyzed (Wang et al , ). Interestingly, GATA‐6 was up‐regulated in suprabasal ORS layers in the bulge region from psoriatic lesional scalps, while no differences were observed in GATA‐6‐positive cells from the proximal bulb (Fig EV1C).…”

Runx1 Role in Epithelial and Cancer Cell Proliferation Implicates Lipid Metabolism and Scd1 and Soat1 Activity

“…cDNA synthesis and qRT-PCR was performed as described earlier (45). Primers used are listed in Supplementary Table 2.…”

“…Response factors were calculated with an external standard mixture (GLC462; Nu-Chek Prep, Inc.) and applied to raw areas to correct for differential instrument responses. Percentages of each fatty acid were calculated by dividing the corrected area of individual fatty acid by the corrected area of total fatty acids for each lipid class (45). …”

Loss of Gata6 causes dilation of the hair follicle canal and sebaceous duct

“…Gene expression experiments further showed that Lrig1 and K79 message levels correlate with that of Gata6 , which encodes a zinc finger transcription factor that plays multiple key roles during development . Deletion of Gata6 has been reported to stifle hair regeneration by causing replicative stress in fast‐cycling matrix progenitor cells and can also lead to a reduction in upper hair follicle cells that ordinarily express this protein . Morphological defects in the upper hair follicle, however, have not been described in these mutants.…”