Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs drug target discovery in ankylosing spondylitis
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ABSTRACT:
PROVIDER: EGAS00001006945 | EGA |
REPOSITORIES: EGA
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Project description:Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterised by enthesitis of the spine and sacroiliac joints. Genome-wide association studies have revealed >100 genetic associations but their functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We report differential disease signatures for specific genomic regions from individual -omic modalities and multi-omic integration, showing enrichment at genetically associated loci and evidence for altered monocyte function in AS. We link putative functional SNPs with cognate genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1. We also show how disease-specific functional genomic data can be integrated with GWAS evidence to enhance therapeutic target discovery. This study combines multiple epigenetic and transcriptional analysis with GWAS to identify cell types, candidate drug target genes and transcriptional regulation of likely pathogenic relevance.
| EGAS00001006233 | EGA
Project description:Genome-wide association studies (GWAS) have identified over 300 loci associated with the inflammatory bowel diseases (IBD), but putative causal genes for most are unknown. We conducted the largest disease-focused expression quantitative trait loci (eQTL) analysis using colon tissue from 252 IBD patients to determine genetic effects on gene expression and potential contribution to IBD. Combined with two non-IBD colon eQTL studies, we identified 194 potential target genes for 108 GWAS loci. eQTL in IBD tissue were enriched for IBD GWAS loci colocalizations, provided novel evidence for IBD-associated genes such as ABO and TNFRSF14, and identified additional target genes compared to non-IBD tissue eQTL. IBD-associated eQTL unique to diseased tissue had distinct regulatory and functional characteristics with increased effect sizes. Together, these highlight the importance of eQTL studies in diseased tissue for understanding functional consequences of genetic variants, and elucidating molecular mechanisms and regulation of key genes involved in IBD.
2024-10-16 | GSE279302 | GEO
Project description:Recent meta-analyses of genome wide association studies (GWAS) have identified approximately 150 loci that are associated with coronary artery disease (CAD). To link the causal genes in these loci to functional transcriptional networks, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with human coronary artery smooth muscle cells (HCASMC) to investigate the cellular and molecular program downstream of one CAD associated transcription factor, TCF21. Analysis of the TCF21 downstream target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including growth factor binding (PDGF, VEGF), matrix interactions (“integrin binding,” “cell adhesion”), and smooth muscle contraction (“actin filament-based processes,” “actin cytoskeleton”). Motif searches of peak sequences confirmed the canonical E-box CAGCTG as the likely binding sequence for TCF21, but also identified bZip motifs that coordinate binding of AP1 family transcription factors. Follow-up ChIP-Seq studies verified enriched binding of bZip factors JUN and JUND to TCF21 target loci. Importantly, analysis of the representation of CAD genes among TCF21 target loci showed highly significant enrichment. Further, expression quantitative trait variation mapped to target genes of TCF21 were significantly enriched among variants with low P-values in the GWAS analyses, and single nucleotide polymorphisms within TCF21 peaks were shown to be in linkage disequilibrium with CAD-associated SNPs, suggesting a functional interaction between TCF21 binding and causal variants in other CAD disease loci. Thus, data and analyses presented here provide evidence for a transcriptional regulatory network that links TCF21 function in smooth muscle cells with a number of other CAD-associated genes, and suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.
2015-04-12 | GSE61369 | GEO
Project description:Recent meta-analyses of genome wide association studies (GWAS) have identified approximately 150 loci that are associated with coronary artery disease (CAD). To link the causal genes in these loci to functional transcriptional networks, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with human coronary artery smooth muscle cells (HCASMC) to investigate the cellular and molecular program downstream of one CAD associated transcription factor, TCF21. Analysis of the TCF21 downstream target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including growth factor binding (PDGF, VEGF), matrix interactions (“integrin binding,” “cell adhesion”), and smooth muscle contraction (“actin filament-based processes,” “actin cytoskeleton”). Motif searches of peak sequences confirmed the canonical E-box CAGCTG as the likely binding sequence for TCF21, but also identified bZip motifs that coordinate binding of AP1 family transcription factors. Follow-up ChIP-Seq studies verified enriched binding of bZip factors JUN and JUND to TCF21 target loci. Importantly, analysis of the representation of CAD genes among TCF21 target loci showed highly significant enrichment. Further, expression quantitative trait variation mapped to target genes of TCF21 were significantly enriched among variants with low P-values in the GWAS analyses, and single nucleotide polymorphisms within TCF21 peaks were shown to be in linkage disequilibrium with CAD-associated SNPs, suggesting a functional interaction between TCF21 binding and causal variants in other CAD disease loci. Thus, data and analyses presented here provide evidence for a transcriptional regulatory network that links TCF21 function in smooth muscle cells with a number of other CAD-associated genes, and suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology. We did ChIP-Seq on human coronary artery smooth muscle cells grown in SmGM-2 Smooth Muscle Growth Medium-2 including hEGF, insulin, hFGF-B and FBS, but without antibiotics (Lonza, #CC-3182. We did immunoprecipitations with two antibodies (Sigma HPA013189 and Abcam 49475). We conducted two biological replicates for each antibody, and also did an IgG control for these studies. For these experiments, sequencing was done on an Illumina GAII, single end reads. In separate set of experiments we performed ChIP-Seq for JUN (Ab sc-1694) and JUND (Ab sc-74) with the same HCASMC cells under the same culture conditions. For these studies we did one replicate for each antibody, and also included an IgG control. Sequencing for the JUN and JUND studies was paired ends, on an Illumina HiSeq machine.
2015-04-12 | E-GEOD-61369 | biostudies-arrayexpress
Project description:Background: Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. This is largely a result of the findings that over 90% of GWAS variants map outside of protein-coding DNA, and instead are enriched in cell type and stimulation-specific gene regulatory regions. Results: Here, we use a disease-focused Capture Hi-C (CHi-C) experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. For one locus, uniquely, we combine further epigenomic evidence to demonstrate how a psoriasis-associated region forms a functional interaction with the distant (>500 kb) KLF4 gene. This interaction occurs between the gene and active enhancers in HaCaT cells, but not in My-La cells. We go on to investigate this long-distance interaction further with Cas9 fusion protein-mediated chromatin modification (CRISPR activation) coupled with RNA-seq, demonstrating how activation of the psoriasis associated enhancer upregulates known genes in the KLF4 pathway, specific to skin cells and apoptosis. Conclusions: Taken together, our study design provides a robust pipeline to follow up GWAS disease associated variants and implicate the causal genes, cell types, direction of effect and consequences, which are vital next steps for the functional translation of genetic findings into clinical benefit.
2020-04-10 | GSE137906 | GEO
Project description:Genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with diseases of the colon including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). However, the functional role of many of these SNPs is largely unknown and tissue-specific resources are lacking. Expression quantitative trait loci (eQTL) mapping identifies target genes of disease-associated SNPs. Here, we comprehensively map eQTLs in the human colon, assess their relevance for GWAS of colonic diseases and provide functional characterization.
2014-04-15 | GSE56789 | GEO
Project description:The identification of target genes at genome-wide association study (GWAS) loci is a major obstacle for GWAS follow-up. To identify candidate target genes at the 16 known endometrial cancer GWAS risk loci, we performed HiChIP chromatin looping analysis of endometrial cell lines. To enrich for enhancer-promoter interactions, a mechanism through which GWAS variation may target genes, we captured loops associated with H3K27Ac histone, characteristic of promoters and enhancers. Analysis of HiChIP loops contacting promoters revealed enrichment for endometrial cancer GWAS heritability and intersection with endometrial cancer risk variation identified 103 HiChIP target genes at 13 risk loci. Expression of four HiChIP target genes (SNX11, SRP14, HOXB2 and BCL11A) was associated with risk variation, providing further evidence for their regulation. Network analysis functionally prioritized a set of proteins that interact with those encoded by HiChIP target genes, and this set was enriched for pan-cancer and endometrial cancer drivers. Lastly, HiChIP target genes and prioritized interacting proteins were over-represented in pathways related to endometrial cancer development. In summary, we have generated the first global chromatin looping data from endometrial cells, enabling analysis of all known endometrial cancer risk loci and identifying biologically relevant candidate target genes.
2020-04-13 | GSE137936 | GEO
Project description:The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across¬ distinct cell-types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer’s Disease (AD), accessible through our intuitive web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU. We describe cis-regulatory relationships in specific cell-types at AD risk loci defined by genome wide association studies (GWAS), demonstrating the utility of this multi-omic single-nucleus approach. Trajectory analysis of glial populations identified disease-relevant transcription factors, like SREBF1 and their regulatory targets. Further, we introduce scWGCNA, a co-expression network analysis strategy robust to the sparsity of single-cell data, to perform a systems-level meta-analysis of AD transcriptomics.
2021-05-12 | GSE174367 | GEO
Project description:Genome-wide association studies (GWAS) have identified hundreds of susceptibility loci for chronic and inflammatory disease phenotypes in humans. There is increasing evidence that chronic inflammation is a crucial driver in the pathogenesis of cardiovascular diseases (CVD), which may be genetically determined. To understand the genetic architecture underlying chronic inflammation and CVD we performed a systematic analysis of (1) common risk alleles coming from published GWAS, (2) of protein-protein interaction (PPI) networks informed by (3) gene expression data with a defined molecular target involved in the inflammatory processes promoting CVD, MRP8. (4) through analysis of integrated haplotype scores (iHS) and FST values in HapMap phase 2 data, we investigated whether recent selection pressure acting upon inflammatory genes affected CVD susceptibility loci. Our findings provide significant evidence for a PPI network, which connects inflammatory and cardiovascular susceptibility genes, and establish a genetic framework of inflammatory CVD. 41.59% of PPI genes are associated with immune functions. 28.3% of integrated genes can be linked to both, an inflammatory and cardiovascular disease phenotype. Interestingly, CDKN2B, and CELSR2/PSRC1/MYBPHL/SORT1, unequivocally replicated CVD loci, are integrated within this network as are several SNPs located in transcription factor recognition sequences, i.e. NFKB1, STAT3, which are key factors in inflammation. Finally, we observed a significant enrichment of inflammatory variants within CVD cluster loci that are targets of selection. Overall, 32 genes exhibit traces of selection, 16 of which are part of the PPI, further suggesting that recent selective sweeps may have affected the genomic architecture underlying CVD. 6 samples, no replicates.
2015-09-01 | E-GEOD-54989 | biostudies-arrayexpress
Project description:Drug-Induced-Liver-Injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market because of inability to identify potential patients prior to clinical testing. Here, we approached a polygenic risk score (PRS) based strategy by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies (GWAS). The PRS predicted the susceptibility to DILI in patients in a clinical trial, and in multi-donor derived primary hepatocytes and stem cell-derived organoids. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress alleviated by a potent antioxidant. Furthermore, hepatocytic transcriptomic signatures related to polygenic score identified potential drugs with clinical DILI evidence through in silico 941 compound screening. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architectures underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed “polygenicity-in-a-dish” strategy potentially will contribute to prospective designs of safer, more efficient, and robust clinical trials.
2020-09-07 | GSE152447 | GEO