Cell-state-specific regulatory roles of the H2AZ-SRCAP chromatin remodeling axis in epidermal tissue homeostasis

Summary: Dysregulation of chromatin remodeling has been increasingly recognized in the pathogenesis of various diseases such as cancer, yet the roles of chromatin remodeling in skin epidermal homeostasis and carcinogenesis remain under-explored. In this study, we focus on the chromatin remodeling process of depositing the histone variant H2AZ in epidermal homeostasis. Epidermal homeostasis requires both progenitor maintenance and the activation of terminal differentiation process. In the progenitor state, H2AZ is highly expressed, and requires the actions of the chromatin remodeler SRCAP to be deposited into chromatin. We found that the high H2AZ expression as well as the intact function of SRCAP are both essential for maintaining the regenerative capacity of epidermal progenitors. High H2AZ levels not only modulate the genes related to extracellular matrix organization and cell adhesion, but also play essential roles in maintaining nuclear-envelope integrity and counteracting DNA damage. Using a targeted inhibitor screen, we identified both MEK/ERK and AKT/mTOR as key upstream pathways sustaining the high expression of both H2AZ and SRCAP in the progenitor state. Inhibition of these pathways drastically reduced H2AZ’s chromatin incorporation, with disrupted nuclear integrity and increased DNA damage foci. In the differentiation process, H2AZ is downregulated at both the mRNA and protein levels. H2AZ’s chromatin incorporation is also drastically reduced. Surprisingly, we found that the residual levels of H2AZ as well as its remodeler SCRAP play essential roles in the differentiation process, by modulating largely distinct sets of genes as compared to the progenitor state, including the activation of epidermal barrier-function genes. Taken together, our findings demonstrate the cell-state-specific roles of the essential SRCAP-H2AZ axis in both progenitor maintenance and the terminal differentiation process. As SRCAP is frequently mutated in both cSCC and BCC, our findings provide new insights into understanding the impact of SRCAP mutations in these two types of skin cancers. Stephenie Droll¹, Xiaomin Bao¹ 1. Northwestern University, Evanston, IL, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics