Identification of disease-specific regulatory networks in prurigo nodularis versus atopic dermatitis through ATAC/RNA single-nucleus profiling

Prurigo Nodularis (PN) is a chronic neuroimmune skin disorder characterized by chronic itch and multiple pruriginous nodules, and is related to atopic dermatitis (AD). While different transcriptomic studies have been conducted, the regulatory mechanisms and differences between PN and AD remain poorly understood. We aimed to uncover shared and distinct regulatory mechanisms between PN and AD. Specifically, we evaluated how molecular factors driving the distinction between lesional and non-lesional skin differ in these two diseases. We profiled gene expression and chromatin accessibility at the single-nuclei level from paired lesional and non-lesional skin samples of four PN patients and five AD patients. We utilized joint modeling and pseudobulk techniques to identify disease specific regulatory network. Our results illustrate that the epigenomic alterations in PN were more numerous and greater magnitude compared to AD skin. PN-biased cis-regulatory elements (CREs) showed correlation with PN-biased differentially expressed genes (DEGs) in the same cell type, and we revealed 199 regulatory modules specific to PN in contrast to 3 modules specific to AD. We also identified PN-specific AP-1-induced regulatory module that induces RUNX2 in fibroblasts, confirmed by immunohistochemistry and immunofluorescence staining, suggestive of its contribution to fibrosis in PN. This study provides a chromatin-RNA-expression atlas and underscores its efficacy in revealing distinct regulatory mechanisms inherent to PN and AD. We highlight distinct epigenomic and transcriptomic regulatory networks in PN, revealing potential driver of PN-associated fibrosis.