Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23

McGovern, Amanda; Schoenfelder, Stefan; Martin, Paul; Massey, Jonathan; Duffus, Kate; Plant, Darren; Yarwood, Annie; Pratt, Arthur G.; Anderson, Amy E.; Isaacs, John D.; Diboll, Julie; Thalayasingam, Nishanthi; Ospelt, Caroline; Barton, Anne; Worthington, Jane; Fraser, Peter; Eyre, Stephen; Orozco, Gisela

doi:10.1186/s13059-016-1078-x

Cited by 92 publications

(82 citation statements)

References 101 publications

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“…Genome-wide association studies (GWAS) in the last decade have associated 324 distinct genomic regions to at least one and often several autoimmune diseases ( http://www.immunobase.org ). The majority of associated variants lie outside genes [1] and presumably tag regulatory variants acting on nearby or more distant genes [2,3] . Progress from GWAS discovery to biological interpretation has been hampered by lack of systematic methods to define the gene(s) regulated by a given variant.…”

Section: Introductionmentioning

confidence: 99%

Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Burren

Garćıa

Javierre

et al. 2017

Preprint

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BackgroundAutoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4+ T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes.ResultsWithin four hours, activation of CD4+ T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA, where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach.ConclusionsOur systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes.

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Section: Introductionmentioning

confidence: 99%

Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Burren

Garćıa

Javierre

et al. 2017

Preprint

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“…For example, using Hi-C, a recent study demonstrated that the non-coding region on chromosome 6 containing a variant that has been associated with RA and psoriasis, interacts not only with the promoter of TNFAIP3, the closest gene, but also with IL20RA. 48 Furthermore, a comprehensive examination of 17 human primary blood cell types found an enrichment of autoimmune disease SNPs in Hi-C domains in lymphoid cells compared with myeloid cells. 49 The authors identified that the majority of identified genes (76%) had not been previously linked with immune-mediated diseases.…”

Section: Co-localization Of Snps With Chromatin Marks Points To Diseamentioning

confidence: 99%

Immunogenomic approaches to understand the function of immune disease variants

2017

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SummaryMapping hundreds of genetic variants through genome wide association studies provided an opportunity to gain insights into the pathobiology of immune‐mediated diseases. However, as most of the disease variants fall outside the gene coding sequences the functional interpretation of the exact role of the associated variants remains to be determined. The integration of disease‐associated variants with large scale genomic maps of cell‐type‐specific gene regulation at both chromatin and transcript levels deliver examples of functionally prioritized causal variants and genes. In particular, the enrichment of disease variants with histone marks can point towards the cell types most relevant to disease development. Furthermore, chromatin contact maps that link enhancers to promoter regions in a direct way allow the identification of genes that can be regulated by the disease variants. Candidate genes implicated with such approaches can be further examined through the correlation of gene expression with genotypes. Additionally, in the context of immune‐mediated diseases it is important to combine genomics with immunology approaches. Genotype correlations with the immune system as a whole, as well as with cellular responses to different stimuli, provide a valuable platform for understanding the functional impact of disease‐associated variants. The intersection of immunogenomic resources with disease‐associated variants paints a detailed picture of disease causal mechanisms. Here, we provide an overview of recent studies that combine these approaches to identify disease vulnerable pathways.

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“…Recently, there has been a growing interest in using chromatin conformation and other functional genomics techniques to describe these disease-associated loci and identify the genes that are affected by them. Previous studies have used techniques such as Capture Hi-C and HiChIP to link the genes that physically interact with disease associated loci (Dryden et al 2014;Jäger et al 2015;Martin et al 2015Martin et al , 2016Cairns et al 2016;McGovern et al 2016;Mumbach et al 2017).…”

Section: Introductionmentioning

confidence: 99%

An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

Shi

Ray-Jones

Ding

et al. 2020

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In the last 15 years Genome wide association studies (GWAS) have uncovered the genetic factors that contribute to disease risk for many disorders, yet the biological significance of many of these associations remain unclear. This is because about 90% of these variants are predicted to affect regulatory elements that are highly cell-type specific and can affect distal genes through chromatin interaction mechanisms and, therefore, understanding their role in disease is challenging.Previous studies have attempted to use chromatin conformation methods to describe the functional mechanism in disease associated loci. However, the majority of these studies have focused on cell lines derived from blood, which might not be the most relevant cell lines for dermatological conditions.Here, we generated HiChIP for H3K27ac, Hi-C and RNA-seq datasets from a keratinocyte and a skinplaque derived CD8+ T cell line. We studied their active chromatin conformation with the aim to identify biological mechanisms that could be affected by variants associated with skin related diseases: psoriasis (Ps), psoriatic arthritis (PsA), systemic sclerosis (SSc), melanoma and atopic dermatitis.In our analysis we show that HiChIP interactions provide functional evidence for gene regulation by showing that enhancers linked to genes that respond to IFN-γ stimulation are strongly enriched for motifs for TFs related to the stimulation. We also show that by using chromatin conformation we can recall 53% of eQTLs identified by GTEx in skin.In addition to our datasets, we integrated public datasets for a B cell-like lymphoblastoid cell line and primary CD4+ T cells to expand our analysis to include GWAS variants associated with the aforementioned diseases likely to be mediated specifically by B cells and CD4+ T cells (such as in systemic sclerosis and melanoma). We then identified the numerous genes that interact with GWAS variants associated and show that these genes strongly enrich for pathways that are related to the trait studied. For example, the top enriched pathways for autoimmune conditions such as PsA and psoriasis included responses to cytokines and T cell regulation, whereas for melanoma they were related to replicative senescence.We show examples of how our analysis can inform changes in the current description of a few psoriasis associated risk loci. For example, the variant rs10794648, which had previously been assigned to IFNLR1, was linked to GRHL3 in our dataset, a gene essential in skin repair and development. This can indicate a renewed importance of skin related factors in the risk of disease.In conclusion, this study allows us to further characterize disease risk loci by using novel chromatin conformation techniques, which can help identify the genes that are putatively involved in disease and has the potential to identify therapeutic targets.

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Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23

Cited by 92 publications

References 101 publications

Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Immunogenomic approaches to understand the function of immune disease variants

An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

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