Skin Epidermal Progenitor Maintenance by the SRCAP-H2A.Z Axis Downstream to Extracellular Signal-Regulated Kinase and...

Epidermal progenitor function is crucial for supporting continuous skin epidermal renewal. How progenitors assimilate inputs from their niche to sustain their function is incompletely defined. In this study, we examine the role of the histone H2A variant, H2A.Z, and the adenosine triphosphate-dependent chromatin remodeling complexes that regulate its occupancy. We show that H2A.Z expression and chromatin occupancy are significantly diminished during keratinocyte differentiation. Although 2 chromatin remodelers are known to deposit H2A.Z, we find that SRCAP is essential for H2A.Z deposition in epidermal progenitors, whereas EP400 is dispensable. Both H2A.Z isoforms, H2AZ1 and H2AZ2, are essential for progenitor proliferation because knockdown of either isoform induces DNA damage and deforms nuclear morphology. Although H2A.Z is greatly reduced in differentiation, we find that the residual H2A.Z and SRCAP continue to maintain the nuclear integrity of differentiating keratinocytes. Because growth factor-induced signaling pathways play pivotal regulatory roles in progenitor maintenance and differentiation, we performed a targeted inhibitor screen to determine whether these pathways might influence H2A.Z. Inhibition of extracellular signal-regulated kinase or mTOR signaling significantly reduces H2A.Z chromatin occupancy and leads to deformed nuclear morphology. This study provides an example of how signaling inputs are linked to chromatin remodeling, supporting epidermal progenitor maintenance.