Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases

Abstract

Immune disease variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states is unknown. We stimulated T cells and macrophages in the presence of thirteen cytokines and profiled active and open chromatin regions. T cell activation induced major chromatin remodeling, while cytokines fine-tuned the Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Activation-induced re-organization of chromatin in human T cells

“…It entailed extensive changes in chromosome accessibility in regions enriched for regulatory elements and eRNAs, immune system-associated SNPs and TFBSs recognized by TFs involved in T cell development, activation or proliferation. What we demonstrate in human T cells parallels what has been described in other systems [12–14,35,36] , namely that changes in chromatin accessibility in response to external cues identify active regulatory regions likely to be critical for transcriptional responses. Furthermore, we show that a T cell activation uncovers many additional regulatory regions likely to be associated with the immune response.…”

“…T cell activation is likely to be instructive of how coordinate changes in chromatin structure orchestrate gene expression programs that underlie rapid and often lifesaving responses. It was recently shown that T cell activation is associated with marked reorganization of chromatin structure at the level of accessibility (measured by ATAC-seq) [12–14] and, separately, conformation (measured by promoter capture-Hi-C) [15] . The present study is the first to analyse genome-wide chromosome conformation in conjunction with chromatin accessibility and whole transcriptome expression, to understand how coordinated changes in higher- and lower-order chromatin structures are linked to gene expression in response to T cell activation.…”

Three-dimensional genome structure and chromatin accessibility reorganization duringin vivoinduction of human T cell tolerance

“…First, the species of T cells are different. Second, different methods, for example, blockade of costimulatory signals in mice by others (Liu et al, 2019) and treatment of healthy donors with G-CSF in our study (Jun et al, 2004), for tolerance induction via different signaling pathways might lead to differences in gene and TF expression (Liu et al, 2019; Soskic et al, 2019; Zhu and Paul, 2010). Overall, our study not only confirmed tolerance-inducing genes and TFs in human tolerant T cells, which were first observed in a mouse model, but also provided a platform to find novel genes, such as KLF-9.…”

Resolving mechanisms of immune-mediated disease in primary CD4 T cells

“…Several of these loci cannot be resolved by fine-mapping 2–4 . Gene deserts were selected because: (1) less is known about how these predispose to disease compared to regions containing candidate genes, (2) other non-coding mechanisms (such as splicing effects 28 ) are unlikely to account for these associations, and (3) many of these contain epigenetic marks consistent with enhancer activity 9, 18, 29 . To maximise the genomic context tested around each SNP, we designed 3 overlapping constructs for every SNP allele 12 , and synthesised additional oligonucleotides to test combinations of risk alleles if more than one SNP could be assayed within the same construct.…”

“…Here, we adapt an MPRA for use in resting and stimulated primary CD4 T cells – the cell-type whose regulatory DNA is most highly enriched for immune-mediated disease SNPs 2, 16–18 . We use this method to simultaneously test individual candidate SNPs from 14 immune disease-associated gene deserts for expression-modulating activity.…”