Unraveling Epigenetic and Transcription Control in Understudied Skin Types

Summary Skin diseases exhibit varying prevalence, severity, and responses across groups of different ancestry, yet the underlying reasons remain unclear. A recent study highlighted that hundreds of genes are uniquely expressed in the skin of healthy individuals of African American ancestry compared to those of European, indicating the profound diversity within the human species. DNA regulatory elements, including promoters and enhancers, are crucial in controlling gene expression by acting as switches to turn genes on or off. However, most studies on transcriptional control of epidermal keratinocytes have been done in European ancestry populations, thus limiting the utility of the results across a variety of human populations. This R21 application is submitted in response to NOT-AR-24-009: Accelerating Research in Understudied Skin Types and is focused on the special interest research topic “using functional genomics, epigenomics, and transcriptomics to identify lead candidate genes and transcripts associated with increased prevalence and severity of skin diseases in patients with understudied skin types.” In response to the NOT-AR-24-009, we will test the hypothesis that the observed differences in gene expression in skin cells from different ancestral backgrounds are due to the variation in DNA regulatory elements. We assembled a multi-disciplinary team of clinicians, biostatisticians, and bioinformaticians to test this hypothesis. Our team has access to human skins collected from healthy individuals of different ancestry. We developed a flow-cytometry-based strategy to isolate epidermal keratinocytes from human skin. We also refined the ATAC-seq and CUT&RUN assay using isolated epidermal cells to identify DNA regulatory elements. Armed with these technological advancements, we will identify common and unique DNA regulatory elements in epidermal cells obtained from individuals of different ancestry. By integrating our findings with existing GWAS data, our goal is to pinpoint SNPs within these regulatory elements associated with atopic dermatitis, a chronic skin inflammatory condition with a higher severity among individuals of African American and Asian ancestry. We will then functionally validate the identified DNA regulatory elements and SNPs located in these regions on controlling gene expression by performing the Massively Parallel Reporter Assay. Our focus on healthy skin samples is intended to establish a fundamental understanding of transcriptional and epigenetic differences in epidermal keratinocytes in individuals of understudied skin types, which is one of the priorities of NOT-AR-24-009. Uncovering these differences will provide much-needed information on differences in gene expression observed in different skin types and can contribute to understanding the different presentations of various skin diseases in groups of different ancestry.