Epigenomic Characterization of Fibroblasts in Darier Disease Identifies Cross-cell-type Regulatory Gene Signatures

Darier disease is a monogenic acantholytic derma-tosis caused by mutations in ATP2A2 that primarily disrupt keratinocyte calcium homeostasis. Whether dermal fibroblasts harborharbour disease-associated epigenetic alterations remainremains uncharacterized. In this study, we performed genome-wide DNA methy-lation profiling on primary fibroblasts from lesional and non-lesional skin, followed by STRING protein-protein interaction network analysis to identify regulatory hub genes. Hub gene expression was validated by qPCR and cross-referenced with single-cell RNA-seq data from healthy skin and published RNA-seq data from Darier disease keratinocytes. Lesional fibroblasts showed consistent, site-specific hyper- and hypomethylation converging on inter-connected regulatory hubs. Hypomethylated hub genes included transcription factors and signalingsignalling integrators while hypermethylated hub genes comprised growth-regulatory and adhesion-related genes. Methylation direction predicted transcriptional output at 10 of 12 hub genes by qPCR. These hub genes are expressed across both fibroblast and keratinocyte populations in healthy skin, and lesional keratinocyte RNA-seq data showed directionally concordant expression changes, indicating shared transcriptional dysregulation across compartments. These findings suggest that Darier disease involves a stable fibroblast epigenetic state with cross-cell-type transcriptional relevance, potentially contributing to dermal-epidermal regulatory disruption in lesional skin.