High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes
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ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE198047 | GEO | 2023/07/28
REPOSITORIES: GEO
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Project description:Genome-wide association studies (GWASs) have identified thousands of single nucleotide polymorphisms (SNPs) associated with human traits and diseases. But because the vast majority of these SNPs are located in the noncoding regions of the genome their risk promoting mechanisms are elusive. Employing a new methodology combining cistromics, epigenomics and genotype imputation we annotate the noncoding regions of the genome in breast cancer cells and systematically identify the functional nature of SNPs associated with breast cancer risk. Our results demonstrate that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 and ESR1 and the epigenome of H3K4me1 in a cancer and cell-type-specific manner. Furthermore, the majority of these risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, which results in allele-specific gene expression, exemplified by the effect of the rs4784227 SNP on the TOX3 gene found within the 16q12.1 risk locus. Examination of histone modification H3K4me2 in untreated and E2 treated cells
2012-08-17 | E-GEOD-31151 | biostudies-arrayexpress
Project description:Genome-wide association studies (GWASs) have identified thousands of single nucleotide polymorphisms (SNPs) associated with human traits and diseases. But because the vast majority of these SNPs are located in the noncoding regions of the genome their risk promoting mechanisms are elusive. Employing a new methodology combining cistromics, epigenomics and genotype imputation we annotate the noncoding regions of the genome in breast cancer cells and systematically identify the functional nature of SNPs associated with breast cancer risk. Our results demonstrate that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 and ESR1 and the epigenome of H3K4me1 in a cancer and cell-type-specific manner. Furthermore, the majority of these risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, which results in allele-specific gene expression, exemplified by the effect of the rs4784227 SNP on the TOX3 gene found within the 16q12.1 risk locus.
2012-08-17 | GSE31151 | GEO
Project description:High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes
| PRJNA813523 | ENA
Project description:Most variants associated to diseases are located in non-coding regions of the genome, and are thought to be regulatory in nature. Cis-regulatory SNPs (cis-rSNPs) impacting transcription can be identified through the mapping of differences in allelic expression (AE). We mapped common cis-rSNPs of protein coding and non-coding genes in 3 distinct cell-types. We show 70% sharing across tissues and similar genetically controlled transcription for protein-coding genes and lincRNAs. Candidate cis-rSNPs altering the expression of 42 non-coding RNA overlap SNPs underlying GWAS associations for 39 diseases. We uncover a new class of cis-rSNPs leading to disruption of footprint-derived de novo motifs, predominantly bind by repressive factors and implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide proof-of-principle for a new approach for genome-wide functional validation of transcription factor – SNP interactions. We perturbed NFκB action in lymphoblasts and identified 489 cis-regulated transcripts with altered AE after NFkB perturbation. Altogether, we performed a comprehensive analysis of cis-variation in four cell-populations, and provide new tools for the identification of functional variants associated to complex diseases.
2014-11-03 | GSE53837 | GEO
Project description:Most variants associated to diseases are located in non-coding regions of the genome, and are thought to be regulatory in nature. Cis-regulatory SNPs (cis-rSNPs) impacting transcription can be identified through the mapping of differences in allelic expression (AE). We mapped common cis-rSNPs of protein coding and non-coding genes in 3 distinct cell-types. We show 70% sharing across tissues and similar genetically controlled transcription for protein-coding genes and lincRNAs. Candidate cis-rSNPs altering the expression of 42 non-coding RNA overlap SNPs underlying GWAS associations for 39 diseases. We uncover a new class of cis-rSNPs leading to disruption of footprint-derived de novo motifs, predominantly bind by repressive factors and implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide proof-of-principle for a new approach for genome-wide functional validation of transcription factor M-bM-^@M-^S SNP interactions. We perturbed NFM-NM-:B action in lymphoblasts and identified 489 cis-regulated transcripts with altered AE after NFkB perturbation. Altogether, we performed a comprehensive analysis of cis-variation in four cell-populations, and provide new tools for the identification of functional variants associated to complex diseases. Mapping cis-rSNPs across 3 distinct cell types in humans
2014-11-03 | E-GEOD-53837 | biostudies-arrayexpress
Project description:Noncoding SNPs decrease expression of FABP5 during COPD exacerbations
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Project description:Genome-wide association studies implicate multiple loci in risk for systemic lupus erythematosus (SLE), but few contain exonic variants, rendering systematic identification of non-coding variants essential to decoding SLE genetics. We utilized SNP-seq and bioinformatic enrichment to interrogate 2180 single-nucleotide polymorphisms (SNPs) from 87 SLE risk loci for potential binding of transcription factors and related proteins from B cells. 52 SNPs that passed initial screening were tested by electrophoretic mobility shift (EMSA) and luciferase reporter assays. To identify binding of transcription factors and/or other nuclear proteins in an allele-determined manner, we employed pulldown using nuclear extract from Daudi cells and silver staining in SNPs that had exhibited allele-specific differential binding by EMSA. Each pulldown product for each allele of the five high-probability SNPs (rs2297550 C/G, rs13213604 C/G, rs276461 T/C, rs9907955 C/T, rs7302634 T/C) was evaluated by mass spectrometry (MS) to identify binding nuclear proteins, yielding a set of candidate proteins for each.
2024-08-02 | PXD048367 | Pride
Project description:Background: Expression quantitative trait loci (eQTL) studies are a valuable approach for identifying genetic variants correlated with gene expression. However, identifying the causal variants is challenging due to linkage disequilibrium amongst variants in the same haplotype block. In this study, we aim to identify functional SNPs in key regulatory regions that alter transcriptional regulation and thus, potentially impact cellular function. The majority of disease-associated single-nucleotide polymorphisms (SNPs) are located in regulatory regions, which can result in allele-specific binding (ASB) of transcription factors and differential expression of the target gene alleles. Here, we present regSNPs-ASB, a generalized linear model-based approach to accurately identify regulatory SNPs that are located in transcription factor binding sites from ATAC-seq data. Results: Using regSNPs-ASB, we identified 53 regulatory SNPs in human MCF-7 breast cancer cells and 125 regulatory SNPs in human mesenchymal stem cells (MSC). By integrating the regSNPs-ASB output with RNA-seq experimental data and publicly available chromatin interaction data from MCF-7 cells, we found that these 53 regulatory SNPs were associated with 74 potential target genes and that 32 (43%) of these genes showed significant allele-specific expression (ASE). By comparing all of the MCF-7 and MSC regulatory SNPs to the eQTLs in the Genome-Tissue Expression (GTEx) Project database, we found that 30% (16/53) of the regulatory SNPs in MCF-7 and 43% (52/122) of the regulatory SNPs in MSC were also eQTLs. The enrichment of regulatory SNPs in eQTLs indicated that many of them are likely responsible for allelic differences in gene expression (chi-square test, p-value < 0.01). In sum, we conclude that regSNPs-ASB is a useful tool for identifying causal variants from ATAC-seq data. This new computational tool will enable efficient prioritization of genetic variants identified as eQTL for further studies to validate their causal regulatory function. Ultimately, identifying causal genetic variants will further our understanding of the underlying molecular mechanisms of disease and the eventual development of potential therapeutic targets.
2020-02-14 | GSE145245 | GEO
Project description:Most of the millions of single-nucleotide polymorphisms (SNPs) in the human genome are non-coding, and many overlap with putative regulatory elements. Genome-wide association studies have linked many of these SNPs to human traits or to gene expression levels, but rarely with sufficient resolution to identify the causal SNPs. Functional screens based on reporter assays have previously been of insufficient throughput to test the vast space of SNPs for possible effects on enhancer and promoter activity. Here, we have leveraged the throughput of the SuRE reporter technology to survey a total of 5.9 million SNPs, including 57% of the known common SNPs world-wide. We identified more than 30 thousand SNPs that alter the activity of putative regulatory elements, often in a cell-type specific manner. These data indicate that a large proportion of human non-coding SNPs may affect gene regulation. Integration of these SuRE data with genome-wide association studies may help to identify causal SNPs.
2019-04-05 | GSE128325 | GEO
Project description:ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Association between genotyed SNPs and APOC3 response to therapy was conducted We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Genomic DNA extracted from peripheral blood was genotyped using a custom GoldenGate bead array encompassing 384 SNPs (Illumina). Multivariate linear regression and 2-way ANOVA for percent change in apoC-III level were performed between the groups receiving FA alone compared with FA+statin compared with statin alone.
2012-01-11 | E-GEOD-34945 | biostudies-arrayexpress