Chromatin Looping Links Target Genes with Genetic Risk Loci for Dermatological Traits

• DOI: 10.1016/j.jid.2021.01.015
• Publication Date: 2021-02-17T06:46:12Z
• Authors: Chenfu Shi; Helen Ray-Jones; James Ding; Kate Duffus; Yao Fu; Vasanthi Priyadar...; Oliver Gough; Jenny Hankinson; Paul Martin; Amanda McGovern; Annie Yarwood; Patrick Gaffney; Steve Eyre; Magnus Rattray; Richard B. Warren; Gisela Orozco
• Keywords: Skin Diseases/genetics; Chromatin/genetics; Chromatin Assembly and Disassembly/genetics; Receptors, Interferon/genetics; Quantitative Trait Loci; Transcription Factors/genetics; Datasets as Topic; Chromatin Assembly and Disassembly; Polymorphism, Single Nucleotide; Skin Diseases; Chromatin; Linkage Disequilibrium; 3. Good health; DNA-Binding Proteins; Enhancer Elements, Genetic; Cell Line, Tumor; Humans; Original Article; Genetic Predisposition to Disease; Promoter Regions, Genetic; DNA-Binding Proteins/genetics; Genome-Wide Association Study; Receptors, Interferon; Transcription Factors

Chromatin looping between regulatory elements and gene promoters presents a potential mechanism whereby disease risk variants affect their target genes. In this study, we use H3K27ac HiChIP, a method for assaying the active chromatin interactome in two cell lines: keratinocytes and skin lymphoma-derived CD8+ T cells. We integrate public datasets for a lymphoblastoid cell line and primary CD4+ T cells and identify gene targets at risk loci for skin-related disorders. Interacting genes enrich for pathways of known importance in each trait, such as cytokine response (psoriatic arthritis and psoriasis) and replicative senescence (melanoma). We show examples of how our analysis can inform changes in the current understanding of multiple psoriasis-associated risk loci. For example, the variant rs10794648, which is generally assigned to IFNLR1, was linked to GRHL3, a gene essential in skin repair and development, in our dataset. Our findings, therefore, indicate a renewed importance of skin-related factors in the risk of disease.