Epigenetic and transcriptional dysregulation in CD4+ T cells in patients with atopic dermatitis.
Epigenetic and transcriptional dysregulation in CD4+ T cells in patients with atopic dermatitis.
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DOI：
10.1371/journal.pgen.1009973
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发表时间：
2022-05
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
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作者：
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. Gene expression is regulated in stimulated CD4+ T cells in a disease-dependent manner in patients with atopic dermatitis (AD). AD-specific regions of chromatin accessibility and binding of the NFKB1 transcription factor are enriched for AD genetic risk variants. Clinically, CD4+ T cells in the peripheral blood of patients with AD respond to stimulation in a disease- and genotype-dependent manner.
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影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
14.2
作者：
Davidson, Wendy F.;Leung, Donald Y. M.;Plaut, Marshall
通讯作者：
Plaut, Marshall
影响因子：
7
作者：
Atak ZK;Taskiran II;Demeulemeester J;Flerin C;Mauduit D;Minnoye L;Hulselmans G;Christiaens V;Ghanem GE;Wouters J;Aerts S
通讯作者：
Aerts S
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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