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

Abstract

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 nonlesional skin differ in these two diseases. We profiled gene expression and chromatin accessibility at the single-nucleus level from paired lesional and nonlesional skin samples of 4 PN patients and 5 AD patients. We utilized joint modeling and pseudobulk techniques to identify disease specific regulatory network. The epigenomic alterations in PN were more numerous and of greater magnitude compared to AD skin. PN-biased cis-regulatory elements showed correlation with PN-biased differentially expressed genes in the same cell type, and we identified 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.