An integrative epidermal epigenome-transcriptome reference for cytokine regulation

Cytokines serve as pathogenic drivers and therapeutic targets in inflammatory and autoimmune skin diseases. While blood-based cytokine studies have highlighted the importance of genetic and epigenetic regulation, they fail to capture the tissue heterogeneity of skin diseases. To characterize the epigenetic regulation of skin cytokines, we collected and analyzed matched epidermal DNA methylome, transcriptome, and cytokine profiles of 120 healthy individuals, establishing a reference resource that can be applied to external skin disease and treatment datasets. Our analysis identified 4187 differentially methylated probes and 461 differentially methylated and expressed genes associated with skin cytokines, revealing tissue-specific patterns of epigenetic regulation. Using the RNA expression and DNA methylation levels of these differentially methylated and expressed genes, we developed omics risk scores for each cytokine. Notably, transcriptomic scores for 6 cytokines showed relatively higher predictive performance in the discovery cohort (R² range: 30-58%) and showed disease-associated differences when applied to external public datasets. In addition, we developed CytoEpi (https://cytoepi.shinyapps.io/cytoepi/), a web application for broader community access and exploration of these cytokine regulatory insights. Overall, this study establishes a foundational multi-omics reference resource on cytokine regulation in healthy skin and provides a useful resource to advance future research into the mechanisms and treatment of inflammatory skin diseases.