Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• PLoS genetics, 2022-05, Vol.18 (5), p.e1009973

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.