Identifying Causal Genes at the Multiple Sclerosis Associated Region 6q23 Using Capture Hi-C

Martin, Paul; McGovern, Amanda; Massey, Jonathan; Schoenfelder, Stefan; Duffus, Kate; Yarwood, Annie; Barton, Anne; Worthington, Jane; Fraser, Peter; Eyre, Stephen; Orozco, Gisela

doi:10.1371/journal.pone.0166923

Cited by 33 publications

(21 citation statements)

References 40 publications

(38 reference statements)

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“…This, region also exemplifies characteristic 2: candidate causal variants lay in HindIII fragments that interacted with multiple genes. Parallel results have demonstrated co-regulation of multiple PCHi-C interacting genes by a single variant [37], suggesting that disease related variants may act on multiple genes simultaneously, consistent with the finding that regulatory elements can interact with multiple promoters [38][39][40]. This region also shows that clusters of multiple adjacent PIRs can be detected for the same promoter.…”

Section: Exemplar Regionssupporting

confidence: 81%

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: Exemplar Regionssupporting

confidence: 81%

Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Burren

Garćıa

Javierre

et al. 2017

Preprint

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“…Second, reduced DREAM expression in Huntington disease (HD), an incurable neurodegenerative disease characterised by synaptic dysfunction and massive neuronal death, isassociated with early neuroprotection through a mechanism that involves the interaction between DREAM and ATF6 and the inhibition of ATF6 processing (86). Small molecules, like repaglinide or CL888, bind to DREAM and block the interaction with ATF6 increasing the amount of processed ATF6 in the nucleus and improving the unfolded protein response(78). Furthermore, DREAM has a role in glucose-dependent regulation of PDYN expression in pancreatic islet cells.…”

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confidence: 99%

Regulators of A20 (TNFAIP3): new drug-able targets in inflammation

Momtazi

Lambrecht

Naranjo

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

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Persistent activation of the transcription factor Nuclear factor-κB (NF-κB) is central to the pathogenesis of many inflammatory disorders, including those of the lung such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD). Despite recent advances in treatment, management of the inflammatory component of these diseases still remains suboptimal. A20 is an endogenous negative regulator of NF-κB signaling, which has been widely described in several autoimmune and inflammatory disorders and more recently in terms of chronic lung disorders. However, the underlying mechanism for the apparent lack of A20 in CF, COPD, and asthma has not been investigated. Transcriptional regulation of A20 is complex and requires coordination of different transcription factors. In this review we examine the existing body of research evidence on the regulation of A20, concentrating on pulmonary inflammation. Special focus is given to the repressor downstream regulatory element antagonist modulator (DREAM) and its nuclear and cytosolic action to regulate inflammation. We provide evidence that would suggest the A20-DREAM axis to be an important player in (airway) inflammatory responses and point to DREAM as a potential future therapeutic target for the modification of phenotypic changes in airway inflammatory disorders. A schematic summary describing the role of DREAM in inflammation with a focus on chronic lung diseases as well as the possible consequences of altered DREAM expression on immune responses is provided.

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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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Identifying Causal Genes at the Multiple Sclerosis Associated Region 6q23 Using Capture Hi-C

Cited by 33 publications

References 40 publications

Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Regulators of A20 (TNFAIP3): new drug-able targets in inflammation

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

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