The Genetics of Human Skin Disease

The vast majority of polymorphisms for human dermatologic diseases fall in noncoding DNA regions, leading to difficulty interpreting their functional significance. Recent work using chromosome conformation capture technology in combination with chromatin immunoprecipitation (ChIP) has provided a systematic means of linking noncoding variants in active enhancer loci to putative gene targets. Here, we apply H3K27ac HiChIP high-resolution contact maps, generated from primary human T-cell subsets (CD4 þ naïve, T helper type 17, and regulatory T cells), to 21 dermatologic conditions associated with single nucleotide polymorphisms from 106 genome-wide association studies. This "enhancer connectome" identified 1,492 HiChIP gene targets from 542 noncoding SNPs (P 5.0 Â 10 e8). SNP-containing enhancers from inflammatory skin conditions were significantly enriched at the HLA locus and also targeted several key factors from the JAK-STAT signaling pathway, but nonimmune conditions were not. A focused profiling of systemic lupus erythematosus HiChIP genes identified enhancer interactions with factors important for effector CD4 þ T-cell differentiation and function, including IRF8 and members of the Ikaros family of zinc-finger proteins. Our results show the ability of the enhancer connectome to nominate functionally relevant candidates from genome-wide association studyeidentified variants, representing a powerful tool to guide future studies into the genomic regulatory mechanisms underlying dermatologic diseases.

Section: Inflammatory Snps Are Enriched Within Hla Locusmentioning

confidence: 99%

“…Over the past decades, genome-wide association studies (GWASs) have identified a large number of single nucleotide polymorphisms (SNPs) associated with complex dermatologic diseases (DeStefano and Christiano, 2014). However, up to 90% of GWAS-identified SNPs fall in noncoding DNA regions (Altshuler et al, 2008;Edwards et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Enhancer Connectome Nominates Target Genes of Inherited Risk Variants from Inflammatory Skin Disorders

Jeng

Mumbach

Granja

et al. 2019

“…Psoriasis is a complex genetic disease with at least 41 genetic susceptibility loci contributing to the pathogenesis [76], and there continues to be progress towards deciphering the genetics of other skin diseases as well [77]. Considering the additional influence of environmental factors [78], it is tempting to argue that studies focused exclusively on genetically homogenous inbred mice, despite all their advantages, can never succeed in fully replicating human diseases and their complexity [79].…”

Section: Discussionmentioning

confidence: 99%

645 Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis

Michaels

Sutter

Diaconu

et al. 2017

“…In contrast, forward genetics is a phenotype-togene approach that begins with a mutant phenotype of interest and proceeds to the identification of the disrupted gene. Both methods have been used to elucidate genes required for protection against dermatologic disease (DeStefano and Christiano, 2014). Reverse genetics generally involves prior knowledge or speculation as to how a gene may function, which can limit the finding of novel and unexpected pathways leading to a disease phenotype.…”

Section: Introductionmentioning

confidence: 99%

Research Techniques Made Simple: Forward Genetic Screening to Uncover Genes Involved in Skin Biology

McAlpine

Russell

Murray

et al. 2019

The primary goals of modern genetics are to identify disease-causing mutations and to define the functions of genes in biological processes. Two complementary approaches, reverse and forward genetics, can be used to achieve this goal. Reverse genetics is a gene-driven approach that comprises specific gene targeting followed by phenotypic assessment. Conversely, forward genetics is a phenotype-driven approach that involves the phenotypic screening of organisms with randomly induced mutations followed by subsequent identification of the causative mutations (i.e., those responsible for phenotype). In this article, we focus on how forward genetics in mice can be used to explore dermatologic disease. We outline mouse mutagenesis with the chemical N-ethyl-N-nitrosourea and the strategy used to instantaneously identify mutations that are causative of specific phenotypes. Furthermore, we summarize the types of phenotypic screens that can be performed to explore various aspects of dermatologic disease.