Capture-C analysis of RCC-susceptibility loci in 786O renal cancer cell line
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE130988 | GEO | 2019/12/31
REPOSITORIES: GEO
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Project description:Capture-C analysis of RCC-susceptibility loci in 786O renal cancer cell line
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Project description:Genome-wide association studies have been tremendously successful in identifying genetic variants associated with complex diseases. The majority of association signals are intergenic and evidence is accumulating that a high proportion of signals lie in enhancer regions.We use Capture Hi-C to investigate, for the first time, the interactions between associated variants for four autoimmune diseases and their functional targets in B- and T-cell lines. Here we report numerous looping interactions and provide evidence that only a minority of interactions are common to both B- and T-cell lines, suggesting interactions may be highly cell-type specific; some disease-associated SNPs do not interact with the nearest gene but with more compelling candidate genes (for example, FOXO1, AZI2) often situated several megabases away; and finally, regions associated with different autoimmune diseases interact with each other and the same promoter suggesting common autoimmune gene targets (for example, PTPRC, DEXI and ZFP36L1). Capture Hi-C was carried out to characterise the interactions of confirmed susceptibility loci for four autoimmune diseases: rheumatoid arthritis (RA), type 1 diabetes (T1D), psoriatic arthritis (PsA) and juvenile idiopathic arthritis (JIA) with the aim of linking associated variants with disease-causing genes. We have tested the interactions in two complementary experiments: the first, Region Capture, targets regions associated with disease; the second, Promoter Capture, provides independent validation through capturing all known promoters within 500kb of lead associated disease SNPs. All experiments were performed in human T-cell (Jurkat) and B-cell (GM12878) lines in duplicate.
2015-11-24 | E-GEOD-69600 | biostudies-arrayexpress
Project description:Susceptibility loci for IgA nephropathy
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Project description:Genome-wide association studies have identified over 70 common variants that are associated with breast cancer risk. Most of these variants map to non-protein-coding regions; several map to gene deserts, regions of several hundred kb lacking protein-coding genes. We hypothesized that gene deserts harbour long-range regulatory elements that can physically interact with target genes to influence their expression. To test this, we developed Capture Hi-C (CHi-C), which by incorporating a sequence capture step into a Hi-C protocol, allows high-resolution analysis of targeted regions of the genome. We used CHi-C to investigate long-range interactions at three breast cancer gene deserts mapping to 2q35, 8q24.21 and 9q31.2. We identified interaction peaks between putative regulatory elements ("bait fragments") within the captured regions and "targets" that included both protein-coding genes and long non-coding (lnc)RNAs, over distances of 6.6 kb to 2.6 Mb. Target protein-coding genes were IGFBP5, KLF4, NSMCE2 and MYC; target lncRNAs included DIRC3, PVT1 and CCDC26. For two gene deserts we were able to define a set of SNPs that were correlated with the published risk variant and that clustered within the bait end of an interaction peak. Preliminary functional analyses implicate one SNP (rs12613955; 2q35) as a potentially functional variant. Capture Hi-C was carried out in BT483, SUM44, and GM06990 cell lines to investigate breast cancer risk loci 2q35, 8q24.21 and 9q31.2.
2014-08-04 | E-GEOD-55634 | biostudies-arrayexpress
Project description:Genome-wide association studies have been tremendously successful in identifying genetic variants associated with complex diseases. The majority of association signals are intergenic and evidence is accumulating that a high proportion of signals lie in enhancer regions.We use Capture Hi-C to investigate, for the first time, the interactions between associated variants for four autoimmune diseases and their functional targets in B- and T-cell lines. Here we report numerous looping interactions and provide evidence that only a minority of interactions are common to both B- and T-cell lines, suggesting interactions may be highly cell-type specific; some disease-associated SNPs do not interact with the nearest gene but with more compelling candidate genes (for example, FOXO1, AZI2) often situated several megabases away; and finally, regions associated with different autoimmune diseases interact with each other and the same promoter suggesting common autoimmune gene targets (for example, PTPRC, DEXI and ZFP36L1).
2015-11-24 | GSE69600 | GEO
Project description:Genome-wide association studies have identified over 70 common variants that are associated with breast cancer risk. Most of these variants map to non-protein-coding regions; several map to gene deserts, regions of several hundred kb lacking protein-coding genes. We hypothesized that gene deserts harbour long-range regulatory elements that can physically interact with target genes to influence their expression. To test this, we developed Capture Hi-C (CHi-C), which by incorporating a sequence capture step into a Hi-C protocol, allows high-resolution analysis of targeted regions of the genome. We used CHi-C to investigate long-range interactions at three breast cancer gene deserts mapping to 2q35, 8q24.21 and 9q31.2. We identified interaction peaks between putative regulatory elements ("bait fragments") within the captured regions and "targets" that included both protein-coding genes and long non-coding (lnc)RNAs, over distances of 6.6 kb to 2.6 Mb. Target protein-coding genes were IGFBP5, KLF4, NSMCE2 and MYC; target lncRNAs included DIRC3, PVT1 and CCDC26. For two gene deserts we were able to define a set of SNPs that were correlated with the published risk variant and that clustered within the bait end of an interaction peak. Preliminary functional analyses implicate one SNP (rs12613955; 2q35) as a potentially functional variant.
2014-08-04 | GSE55634 | GEO
Project description:Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor. Despite intense study, how this impinges on cancer development is incompletely understood. To test for the impact of genetic signals on this pathway, we aligned human RCC-susceptibility polymorphisms with genome-wide assays of HIF-binding and observed highly significant overlap. Allele-specific assays of HIF binding, chromatin conformation and gene expression together with eQTL analyses in human tumors were applied to mechanistic analysis of one such overlapping site at chromosome 12p12.1. This defined a novel stage-specific mechanism in which the risk polymorphism, rs12814794, directly creates a new HIF-binding site that mediates HIF-1? isoform specific upregulation of its target BHLHE41. The alignment of multiple sites in the HIF cis-acting apparatus with RCC-susceptibility polymorphisms strongly supports a causal model in which minor variation in this pathway exerts significant effects on RCC development.
2017-07-11 | GSE101063 | GEO
Project description:Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor. Despite intense study, how this impinges on cancer development is incompletely understood. To test for the impact of genetic signals on this pathway, we aligned human RCC-susceptibility polymorphisms with genome-wide assays of HIF-binding and observed highly significant overlap. Allele-specific assays of HIF binding, chromatin conformation and gene expression together with eQTL analyses in human tumors were applied to mechanistic analysis of one such overlapping site at chromosome 12p12.1. This defined a novel stage-specific mechanism in which the risk polymorphism, rs12814794, directly creates a new HIF-binding site that mediates HIF-1? isoform specific upregulation of its target BHLHE41. The alignment of multiple sites in the HIF cis-acting apparatus with RCC-susceptibility polymorphisms strongly supports a causal model in which minor variation in this pathway exerts significant effects on RCC development.
2017-07-11 | GSE101062 | GEO
Project description:Fine Mapping of Eight Psoriasis Susceptibility Loci
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Project description:Kidney cancer accounts for more than 100,000 deaths per year world-wide. More than 80% are clear cell tumors (ccRCCs) and the majority are associated with loss of function of the von Hippel Lindau (pVHL) tumor suppressor resulting in upregulation of HIF-{alpha} subunits, and activation of HIF-dependent transcriptional pathways. Recent GWAS studies have discovered RCC-susceptibility loci both within EPAS1 (HIF-2{alpha}) and in an intergenic region of unknown function on 11q13.3. As part of an ongoing study to define the direct transcriptional targets of HIF-2 in renal cancer, we undertook a genome-wide analysis of HIF-2-binding sites in pVHL-defective 786-O cells (that lack functional HIF-1{alpha} due to a truncated transcript) using chromatin immunoprecipitation with antibodies directed against HIF-2{alpha} and its dimerization partner HIF-1{beta}, coupled to high-throughput sequencing (ChIP-seq). Amongst approximately 600 pangenomic HIF-2{beta} ChIP signals, we observed strong binding (ranked 12th by peak height) almost precisely coinciding with the RCC predisposition SNP rs7105934 on 11q13.3. We report binding of HIF-2{alpha} and HIF-1{beta} in 786-O clear cell renal carcinoma cells. 3 samples examined, HIF-2{alpha}, HIF-1{beta} and pre-immune control ChIP.
2012-02-01 | E-GEOD-34871 | biostudies-arrayexpress