Integration of genetic and chromatin modification data pinpoints autoimmune-specific remodeling of enhancer landscape in CD4+ T cells

Abstract

CD4⁺ T cells play a crucial role in adaptive immune responses and have been implicated in the pathogenesis of autoimmune diseases (ADs). Despite numerous studies, the molecular mechanisms underlying T cell dysregulation in ADs remain incompletely understood. Here, we used chromatin immunoprecipitation (ChIP)-sequencing of active chromatin and transcriptomic data from CD4⁺ T cells of healthy donors and patients with systemic lupus erythematosus (SLE), psoriasis, juvenile idiopathic arthritis (JIA), and Graves' disease to investigate the role of enhancers in AD pathogenesis. By generating enhancer-based gene regulatory networks (eGRNs), we identified disease-specific dysregulated pathways and potential downstream target genes of enhancers harboring AD-associated single-nucleotide polymorphisms (SNPs), which we also validated using chromatin-capture (HiC) data and CRISPR interference (CRISPRi) in primary CD4⁺ T cells. Our results suggest that alterations in the regulatory landscapes of CD4⁺ T cells, including enhancers, contribute to the development of ADs and provide a basis for developing new therapeutic approaches.

Keywords: CP: Genomics; T cells; autoimmune diseases; enhancers; epigenetics; gene regulatory networks; genome-wide association studies; transcription factors.