PLoS Genetics (May 2022)

Epigenetic and transcriptional dysregulation in CD4+ T cells in patients with atopic dermatitis.

  • Amy A Eapen,
  • Sreeja Parameswaran,
  • Carmy Forney,
  • Lee E Edsall,
  • Daniel Miller,
  • Omer Donmez,
  • Katelyn Dunn,
  • Xiaoming Lu,
  • Marissa Granitto,
  • Hope Rowden,
  • Adam Z Magier,
  • Mario Pujato,
  • Xiaoting Chen,
  • Kenneth Kaufman,
  • David I Bernstein,
  • Ashley L Devonshire,
  • Marc E Rothenberg,
  • Matthew T Weirauch,
  • Leah C Kottyan

DOI
https://doi.org/10.1371/journal.pgen.1009973
Journal volume & issue
Vol. 18, no. 5
p. e1009973

Abstract

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Atopic dermatitis (AD) is one of the most common skin disorders among children. Disease etiology involves genetic and environmental factors, with 29 independent AD risk loci enriched for risk allele-dependent gene expression in the skin and CD4+ T cell compartments. We investigated the potential epigenetic mechanisms responsible for the genetic susceptibility of CD4+ T cells. To understand the differences in gene regulatory activity in peripheral blood T cells in AD, we measured chromatin accessibility (an assay based on transposase-accessible chromatin sequencing, ATAC-seq), nuclear factor kappa B subunit 1 (NFKB1) binding (chromatin immunoprecipitation with sequencing, ChIP-seq), and gene expression levels (RNA-seq) in stimulated CD4+ T cells from subjects with active moderate-to-severe AD, as well as in age-matched non-allergic controls. Open chromatin regions in stimulated CD4+ T cells were highly enriched for AD genetic risk variants, with almost half of the AD risk loci overlapping AD-dependent ATAC-seq peaks. AD-specific open chromatin regions were strongly enriched for NF-κB DNA-binding motifs. ChIP-seq identified hundreds of NFKB1-occupied genomic loci that were AD- or control-specific. As expected, the AD-specific ChIP-seq peaks were strongly enriched for NF-κB DNA-binding motifs. Surprisingly, control-specific NFKB1 ChIP-seq peaks were not enriched for NFKB1 motifs, but instead contained motifs for other classes of human transcription factors, suggesting a mechanism involving altered indirect NFKB1 binding. Using DNA sequencing data, we identified 63 instances of altered genotype-dependent chromatin accessibility at 36 AD risk variant loci (30% of AD risk loci) that might lead to genotype-dependent gene expression. Based on these findings, we propose that CD4+ T cells respond to stimulation in an AD-specific manner, resulting in disease- and genotype-dependent chromatin accessibility alterations involving NFKB1 binding.