Regulatory Variants in Human Skin Diseases

Stanford University, Stanford CA

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Abstract

REGULATORY VARIANTS IN HUMAN SKIN DISEASE PROJECT SUMMARY Polygenic skin diseases, such as psoriasis, atopic dermatitis, acne vulgaris, and skin cancer, arise from interactions between inherited pathogenic DNA variants and the environment. During the current funding cycle, AR076965 identified 355 noncoding, differentially-active single nucleotide variants (daSNVs) linked to risk for 10 prevalent polygenic skin disorders. These daSNVs alter transcription-directing function and concentrate in the promoters and enhancers of genes critical for epidermal homeostasis, including those involved in epidermal differentiation, inflammation, and gene regulation. This supports a model in which altered regulatory DNA sequence may interact with environmental factors to alter gene expression in ways that predispose to genetically complex disorders. This competing renewal will define the impacts of these daSNVs on their disease- relevant target genes as well as the transcription factors (TFs) whose DNA binding they alter. Prominent among putative daSNV target genes (ptGenes) were those encoding specific epidermal TFs, including IRF6, OVOL1, KLF4, TP63, and STAT3. Each of these TFs plays an essential role in epidermal homeostasis and each acts in a dosage-dependent fashion, suggesting that daSNVs that alter their levels may predispose to the epidermal abnormalities seen in the polygenic skin diseases studied. AR076965 identified daSNVs in the promoters and enhancers of these TFs. Aim I will define the impact of skin disease-linked daSNVs on levels of these essential epidermal TFs in tissue, the degree to which daSNV-altered TF levels impact epidermal gene expression and barrier function, and the gene regulators whose DNA binding these daSNVs alter. Class I major histocompatibility (MHC) genes were also identified as daSNV target genes. Class I MHC proteins mediate peptide antigen presentation and their down-regulation can trigger inflammation via a “missing self” immune response. At the HLA-Cw*06:02 MHC allele, which is the strongest risk locus for psoriasis vulgaris, AR076965 found that multiple daSNVs downregulate HLA-C expression in keratinocytes, but not immune cells and that expression of HLA-C protein, but not HLA-A or HLA-B, is decreased in lesional psoriatic epidermis. AR076965 also observed that HLA-C knockout induces psoriasiform dermatitis in human skin xenografts in vivo, indicating that decreased keratinocyte HLA-C expression can drive cutaneous inflammation and epidermal hyperplasia. Aim II will examine a model in which psoriasis risk daSNVs down-regulate keratinocyte HLA-C levels to enhance cutaneous inflammation and disrupt epidermal homeostasis. This effort will expand insight into how inherited variation in regulatory DNA predisposes to the emergence of the abnormalities in epidermal homeostasis characteristic of prevalent skin diseases.