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

Abstract

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 lymphomaederived CD8þ T cells. We integrate public datasets for a lymphoblastoid cell line and primary CD4þ 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.

Capturing New Disease Genes in Psoriasis and Other Skin Diseases

“…Recent studies have addressed this problem with chromatin conformation capture methods that define which promoters SNP-affected enhancers contact. In their new article in the Journal of Investigative of Dermatology, Shi et al (2021) have added to this body of literature with a chromatin conformation capture approach in keratinocyte (KC) and lymphocyte cell lines, two cell types relevant for common skin diseases, thus refining our understanding of skin disease mechanisms, including those in psoriasis.…”

“…This approach identifies all enhancer-promoter interactions in a given cell type, and by overlapping these data with SNPs identified in GWASs, one can potentially predict the genes whose expression is altered by the SNP (Figure 1a). This was the approach used by Shi et al (2021).…”

“…To simulate the psoriatic KC environment, Shi et al (2021) conducted the experiments with untreated and IFN-g-treated HaCaT cells. IFN-g stimulation altered the expression of over 500 genes, most of which were upregulated.…”

“…To represent the immune component of psoriasis, Shi et al (2021) used MyLa cells (lymphoma CD8 þ T cells) and incorporated data from another study that used naive T cells and a B-cell-like lymphoblastoid line (Mumbach et al, 2017).…”

“…Because enhancers and enhancerpromoter interactions are often celltype specific, it is important to study the effects of disease SNPs in cell types relevant to the disease. With this approach, Shi et al (2021) identified at least four new cell-type-specific SNP interactions with genes not previously linked to psoriasis in genetic studies.…”