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Lymphocyte DNA methylation mediates genetic risk at shared immune mediated disease loci

ABSTRACT: Lymphocyte DNA methylation mediates genetic risk at shared immune mediated disease loci

PROVIDER: PRJNA566108 | ENA |

REPOSITORIES: ENA

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Lymphocyte DNA methylation mediates genetic risk at shared immune mediated disease loci

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-12-17 | GSE137634 | GEO

Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci.

Project description:BackgroundDefining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in the post-genome-wide association study era.ObjectivesWith a focus on rheumatoid arthritis, we sought new insight into genetic mechanisms of adaptive immune dysregulation to help prioritize molecular pathways for targeting in this and related immune pathologies.MethodsWhole-genome methylation and transcriptional data from isolated CD4+ T cells and B cells of more than 100 genotyped and phenotyped patients with inflammatory arthritis, all of whom were naive to immunomodulatory treatments, were obtained. Analysis integrated these comprehensive data with genome-wide association study findings across IMDs and other publicly available resources.ResultsWe provide strong evidence that disease-associated DNA variants regulate cis-CpG methylation in CD4+ T and/or B cells at 37% RA loci. Using paired, cell-specific transcriptomic data and causal inference testing, we identify examples where site-specific DNA methylation in turn mediates gene expression, including FCRL3 in both cell types and ORMDL3/GSDMB, IL6ST/ANKRD55, and JAZF1 in CD4+ T cells. A number of genes regulated in this way highlight mechanisms common to RA and other IMDs including multiple sclerosis and asthma, in turn distinguishing them from osteoarthritis, a primarily degenerative disease. Finally, we corroborate the observed effects experimentally.ConclusionsOur observations highlight important mechanisms of genetic risk in RA and the wider context of immune dysregulation. They confirm the utility of DNA methylation profiling as a tool for causal gene prioritization and, potentially, therapeutic targeting in complex IMD.

| S-EPMC7201180 | biostudies-literature

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Knockdown of ASD risk genes leads to a shared transcriptional signature

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CRISPR screens identify gene targets at breast cancer risk loci [RNA-seq]

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CRISPR screens identify gene targets at breast cancer risk loci [ATAC-seq]

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Shared Genomic Segment Analysis and Tumor Subtyping in High-Risk BrCa Pedigrees

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Shared Genomic Segment Analysis and Tumor Subtyping in High-Risk BrCa Pedigrees

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Chromatin looping links target genes with genetic risk loci for dermatological traits

Project description:Chromatin looping between regulatory elements and gene promoters presents a potential mechanism whereby disease risk variants affect their target genes. Here we use H3K27ac HiChIP, a method for assaying the active chromatin interactome in two cell lines: keratinocytes and skin derived CD8+ T cells. We integrate public datasets for a lymphoblastoid cell line and primary CD4+ T cells and identify gene targets at risk loci for skin-related disorders. Interacting genes enrich for pathways of known importance in each trait, such as cytokine response (psoriatic arthritis, psoriasis) and replicative senescence (melanoma). We show examples of how our analysis can inform changes in the current understanding of multiple psoriasis associated risk loci. For example, the variant rs10794648, which is generally assigned to IFNLR1, was linked to GRHL3 in our dataset, a gene essential in skin repair and development. Our findings, therefore, indicate a renewed importance of skin related factors in the risk of disease.

2020-05-27 | GSE151193 | GEO

Transcription factor-SNP interactome for colorectal cancer risk loci

Project description:A core task to understand the consequences of non-coding single nucleotide polymorphisms (SNP) is to identify their genotype specific binding of transcription factor (TF). Here, we generate a large-scale TF-SNP interaction map for a selection of 116 colorectal cancer (CRC) risk loci and validated TF binding to 10 putatively functional SNPs. Our data further revealed TF binding complexity adjacent to the 116 risk loci, adding an additional layer of understanding to regulatory networks associated with CRC relevant loci.

2017-02-23 | PXD004435 | Pride

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