Journal Article

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

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

2022

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Atopic dermatitis / Binding sites / Biology and Life Sciences / CD4 antigen / CD4-Positive T-Lymphocytes - metabolism / Child / Chromatin / Chromatin - genetics / Cytokines / Deoxyribonucleic acid / Dermatitis / Dermatitis, Atopic - genetics / Disease / DNA / DNA sequencing / Eczema / Environmental factors / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Etiology / Food allergies / Gene expression / Gene loci / Genetic aspects / Genetic transcription / Genomes / Genotype & phenotype / Genotypes / Health aspects / Health risk assessment / Humans / Immunoprecipitation / Lymphocytes / Lymphocytes T / Medicine and Health Sciences / NF-kappa B - metabolism / NF-κB protein / Peripheral blood / Skin diseases / T cells / Transcription factors / Transposase