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Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci

ABSTRACT: Genome-wide association studies have been tremendously successful in identifying genetic variants associated with complex diseases. The majority of association signals are intergenic and evidence is accumulating that a high proportion of signals lie in enhancer regions.We use Capture Hi-C to investigate, for the first time, the interactions between associated variants for four autoimmune diseases and their functional targets in B- and T-cell lines. Here we report numerous looping interactions and provide evidence that only a minority of interactions are common to both B- and T-cell lines, suggesting interactions may be highly cell-type specific; some disease-associated SNPs do not interact with the nearest gene but with more compelling candidate genes (for example, FOXO1, AZI2) often situated several megabases away; and finally, regions associated with different autoimmune diseases interact with each other and the same promoter suggesting common autoimmune gene targets (for example, PTPRC, DEXI and ZFP36L1).

ORGANISM(S): Homo sapiens

PROVIDER: GSE69600 | GEO | 2015/11/24

SECONDARY ACCESSION(S): PRJNA285958

REPOSITORIES: GEO

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Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci

Project description:Genome-wide association studies have been tremendously successful in identifying genetic variants associated with complex diseases. The majority of association signals are intergenic and evidence is accumulating that a high proportion of signals lie in enhancer regions.We use Capture Hi-C to investigate, for the first time, the interactions between associated variants for four autoimmune diseases and their functional targets in B- and T-cell lines. Here we report numerous looping interactions and provide evidence that only a minority of interactions are common to both B- and T-cell lines, suggesting interactions may be highly cell-type specific; some disease-associated SNPs do not interact with the nearest gene but with more compelling candidate genes (for example, FOXO1, AZI2) often situated several megabases away; and finally, regions associated with different autoimmune diseases interact with each other and the same promoter suggesting common autoimmune gene targets (for example, PTPRC, DEXI and ZFP36L1). Capture Hi-C was carried out to characterise the interactions of confirmed susceptibility loci for four autoimmune diseases: rheumatoid arthritis (RA), type 1 diabetes (T1D), psoriatic arthritis (PsA) and juvenile idiopathic arthritis (JIA) with the aim of linking associated variants with disease-causing genes. We have tested the interactions in two complementary experiments: the first, Region Capture, targets regions associated with disease; the second, Promoter Capture, provides independent validation through capturing all known promoters within 500kb of lead associated disease SNPs. All experiments were performed in human T-cell (Jurkat) and B-cell (GM12878) lines in duplicate.

2015-11-24 | E-GEOD-69600 | biostudies-arrayexpress

Genetic Risk Variants for Autoimmune Diseases that Influence Gene Expression in Thymus

Project description:Genome-wide association studies (GWAS) have boosted our knowledge of genetic risk variants in autoimmune diseases (AIDs). Most of the risk variants are located within or near genes with immunological functions, and the majority is found to be non-coding, pointing towards a regulatory role. We have performed a cis expression quantitative trait locus (eQTL) screen to investigate whether single nucleotide polymorphisms (SNPs) associated with AIDs influence gene expression in thymus. Genotyping was performed using the Immunochip and 353 AID associated SNPs were tested against expression of surrounding genes (+/- 1 Mb) from human thymic tissue (N=42). We identified eight genes where the expression was associated with AID risk SNPs at a study-wide level of significance (P < 2.57x10-5). Five genes (FCRL3, RNASET2, C2orf74, SIRPG and SYS1) displayed cis eQTL signals also in other tissues, while for two loci (NPIPB8 and LOC388814), the eQTL signal appear to be thymus-specific. Since many AID risk variants from GWAS have been subsequently fine-mapped in recent Immunochip projects, we explored the overlap between these novel AID risk variants and the thymic eQTL regions. Moreover, we examined the functional annotation of the seven expression altering SNPs (eSNPs). Our study reveals autoimmune risk variants that act as eQTLs in thymus. We have highlighted functional variants within these genetic regions that potentially can represent causal autoimmune risk variants. Total RNA from 42 human thymic samples were obtained from children undergoing cardiac surgery.

2016-01-21 | E-GEOD-77052 | biostudies-arrayexpress

BRBseq of Naïve T cells from Bach2_18del and WT controls

Project description:Genome-wide association studies have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variant(s) within each locus are mostly unknown. Here, we perform high-throughput allele-specific reporter assays to prioritize disease-associated variants for five autoimmune diseases. By examining variants that both promote allele-specific reporter expression and are located in accessible chromatin, we identify 60 putatively causal variants that enrich for statistically fine-mapped variants by up to 57.8-fold. We introduced the risk allele of a prioritized variant (rs72928038) into a human T cell line and deleted the orthologous sequence in mice, both resulting in reduced BACH2 expression. Naïve CD8 T cells from mice containing the deletion had reduced expression of genes that suppress activation and maintain stemness, and, upon acute viral infection, displayed greater propensity to become effector T cells. Our results represent an example of an effective approach for prioritizing variants and studying their physiologically relevant effects.

2022-03-02 | GSE193241 | GEO

Enhancer connectome in primary human cells reveals target genes of disease-associated DNA elements

Project description:The imprecision of linking intergenic mutations to target genes has limited molecular understanding of diverse human diseases. Here, we show H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naïve T cells to either T helper 17 cells or regulatory T cells create subtype-specific enhancer-promoter interactions, specifically at regions of shared DNA accessibility. We provide an atlas for assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. HiChIP target genes are supported by CRISPR interference and activation of enhancers, expression quantitative trait loci, and allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a four-fold expansion of target genes for autoimmune and cardiovascular diseases.

2017-08-28 | GSE101498 | GEO

Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions

Project description:Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements.

2015-08-20 | GSE62742 | GEO

Homo sapiens

Project description:Genetic Risk Variants for Autoimmune Diseases that Influence Gene Expression in Thymus

| PRJNA309337 | ENA

Pathogenic Implications for Autoimmune Mechanisms Derived by Comparative eQTL Analysis of CD4+ Versus CD8+ T cells

Project description:Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13.2 containing the rs1131017 SNP in the RPS26 gene. Most remarkably, we identify a common missense variant in IL27, associated with type 1 diabetes that results in decreased functional activity of the protein and reduced expression levels of downstream IRF1 and STAT1 in CD4+ T cells only. Altogether, our results indicate that eQTL mapping in purified T cells provides novel functional insights into polymorphisms and pathways associated with autoimmune diseases.

2017-02-23 | GSE78840 | GEO

SLEAR predisposes to systemic lupus erythematosus by regulating apoptosis [RNA-Seq]

Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease, and affects all parts of the human body. Genome-wide association studies have been employed to identify susceptibility genes of SLE. However, most of the SLE associated variants are located in the noncoding regions of the human genome. We characterized SLE risk variants in Chinese populations. One of the most significant validated SNP was located in a gene which we named SLEAR. We found SLEAR was enriched in the nucleus and could regulate apoptosis. Apoptosis is a highly regulated process. And misregulation of the process could lead to autoimmune diseases, especially SLE. Our results suggest that SLEAR plays a key role in apoptosis regulation and is associated with SLE predisposition.

2018-04-09 | GSE104382 | GEO

SLEAR predisposes to systemic lupus erythematosus by regulating apoptosis [ChIRP-Seq]

Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease, and affects all parts of the human body. Genome-wide association studies have been employed to identify susceptibility genes of SLE. However, most of the SLE associated variants are located in the noncoding regions of the human genome.We characterized SLE risk variants in Chinese populations. One of the most significant validated SNP was located in a gene which we named SLEAR. We found SLEAR was enriched in the nucleus and could regulate apoptosis. Apoptosis is a highly regulated process. And misregulation of the process could lead to autoimmune diseases, especially SLE. Our results suggest that the SLEAR plays a key role in apoptosis regulation and is associated with SLE predisposition.

2018-04-09 | GSE104479 | GEO

Massively Parallel Reporter Assay Confirms Regulatory Potential of hQTLs and Reveals Important Variants in Lupus and Other Autoimmune Diseases

Project description:We designed a massively parallel reporter assay (MPRA) in an Epstein-Barr virus transformed B cell line to directly characterize the potential for histone post-translational modifications, i.e., histone quantitative trait loci (hQTLs), expression QTLs (eQTLs), and variants on SLE and autoimmune (AI) disease risk haplotypes to modulate regulatory activity in an allele dependent manner. Our study demonstrates that hQTLs, as a group, are more likely to modulate regulatory activity in an MPRA compared to other variant classes tested, including a set of eQTLs previously shown to interact with hQTLs and tested AI risk variants. In addition, we nominate 17 variants (including 11 previously unreported) as putative causal variants for SLE and another 14 for various other AI diseases, prioritizing these variants for future functional studies primary and immortalized B cells. Thus, we uncover important insights into the mechanistic relationships between genotype, epigenetics, and gene expression in SLE and AI disease phenotypes.

2024-03-10 | GSE254502 | GEO

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