Chromatin Interactions in Differentiating Keratinocytes Reveal Novel Atopic Dermatitis and Psoriasis-Associated Genes

Abstract Background Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, two common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWAS). The majority of these variants are in non-coding regions and their target genes remain largely unclear. Objective We sought to understand the effects of these non-coding variants on the development of AD and psoriasis by linking them to the genes they regulate. Methods We constructed genomic 3D maps of human keratinocytes during differentiation using capture Hi-C targeting more >20, 000 promoters and 214 GWAS variants and combined this with transcriptome and epigenomic datasets. We validated our results with reporter assays, CRISPR activation and examination of patient gene expression from previous studies. Results We identified 118 target genes of 82 AD and psoriasis GWAS-variants. Differential expression of 49% (58) of the 118 target genes occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlight AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 genes and provide further evidence for their potential roles in AD and psoriasis. Conclusions Our work focuses on skin barrier pathology through investigation of the interaction profile of GWAS-variants during keratinocyte differentiation. We provide a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the nearest gene to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.