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

J Invest Dermatol. 2019 Mar;139(3):605-614. doi: 10.1016/j.jid.2018.09.011. Epub 2018 Oct 10.


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+ 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 × 10-8). 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+ 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 study-identified variants, representing a powerful tool to guide future studies into the genomic regulatory mechanisms underlying dermatologic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Chromatin
  • Chromatin Immunoprecipitation
  • Connectome
  • Enhancer Elements, Genetic / genetics*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Histones / genetics*
  • Humans
  • Ikaros Transcription Factor / genetics
  • Inflammation / genetics*
  • Interferon Regulatory Factors / genetics
  • Janus Kinases / metabolism
  • Lupus Erythematosus, Systemic / genetics*
  • Polymorphism, Single Nucleotide
  • STAT Transcription Factors
  • Signal Transduction
  • Skin Diseases / genetics*
  • T-Lymphocytes, Regulatory / physiology*
  • Th17 Cells / physiology*


  • Chromatin
  • Histones
  • Interferon Regulatory Factors
  • STAT Transcription Factors
  • interferon regulatory factor-8
  • Ikaros Transcription Factor
  • Janus Kinases