Multi-tissue epigenetic analysis of the osteoarthritis susceptibility locus mapping to the plectin gene PLEC
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA601438 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10898929_1.fastq.gz | Fastqsanger.gz | |||
| SRR10898929_2.fastq.gz | Fastqsanger.gz | |||
| SRR10898930_1.fastq.gz | Fastqsanger.gz | |||
| SRR10898930_2.fastq.gz | Fastqsanger.gz | |||
| SRR10898931_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 15 |
Similar Datasets
Project description:We report an immortalised CRISPR-Cas9 mesenchymal stem cell line knockdown of Plectin, we initally noted that patients with osteoarthritis association single nucelotide polymorphism rs11780978 had a correlation between genotype at rs11780978 and allelic expression imbalance, with a reduced expression of Plectin from the risk allele. We replicated the effect of the risk allele by deleting 26bp from exon 3 of Plectin to generate multiple knockdown lines to assess the molecular phenotype of Plectin knockdown in the cells. Our data suggest that Plectin knockdown was detectable in the RNA-sequencing data but at a significantly lower level compared to control. The knock-down was very efficient at the protein level, with a near total absence of plectin observed. The knock-down impacted on a range of cellular pathways. Of particular note, both the innate and the acquired immune response showed an upregulation, an effect that has been reported on previously in OA for both cartilage and synovium . Downregulation of Wnt signalling was also of interest, as this pathway is critical to cartilage homeostasis. Furthermore, there is growing evidence of an interplay between Wnt signalling and inflammation in joint tissues.
2020-07-07 | GSE143725 | GEO
Project description:ObjectiveIn cartilage, the osteoarthritis (OA) associated single nucleotide polymorphism (SNP) rs11780978 correlates with differential expression of PLEC, and with differential methylation of PLEC CpG dinucleotides, forming eQTLs and mQTLs respectively. This implies that methylation links chondrocyte genotype and phenotype, thus driving the functional effect of this genetic risk signal. PLEC encodes plectin, a cytoskeletal protein that enables tissues to respond to mechanical forces. We sought to assess whether these PLEC functional effects were cartilage specific.MethodCartilage, fat pad, synovium and peripheral blood were collected from patients undergoing arthroplasty. PLEC CpGs were analysed for mQTLs and allelic expression imbalance (AEI) was performed to test for eQTLs. Plectin was knocked down in a mesenchymal stem cell (MSC) line using CRISPR/Cas9 and cells phenotyped by RNA-sequencing.ResultsmQTLs were discovered in fat pad, synovium and blood. Their effects were however stronger in the joint tissues and of comparable effect between these tissues. We observed AEI in synovium in the same direction as for cartilage and correlations between methylation and PLEC expression. Knocking-down plectin impacted on pathways reported to have a role in OA, including Wnt signalling, glycosaminoglycan biosynthesis and immune regulation.ConclusionsSynovium is also a target of the rs11780978 OA association functionally operating on PLEC. In fat pad, mQTLs were identified but these did not correlate with PLEC expression, suggesting the functional effect is not joint-wide. Our study highlights interplay between genetic risk, DNA methylation and gene expression in OA, and reveals clear differences between tissues from the same diseased joint.
| S-EPMC7594932 | biostudies-literature
Project description:Osteoarthritis, a serious joint disease for which we currently have no disease-stratifying or modifying therapy, causes pain and functional disability for almost a quarter of a billion people world-wide. In this study chondrocytes, synoviocytes and peripheral blood from 100 patients with osteoarthritis to construct a deep molecular quantitative trait locus (molQTL) map of the disease for transcriptomics and proteomics.
2020-11-17 | PXD014666 | Pride
Project description:The aim of our study was to characterize the genotypic and phenotypic extent of multi-locus imprinting disturbances. Therefore, we analyzed the DNA methylation pattern of 37 individuals with different DNA methylation disturbances. Of these 37 individuals 17 were previously diagnosed with a multi-locus methylation disturbance (MLID) and the remaing 20 were diagnosed with a typical single locus imprinting disorder (SLID). We compared the DNA methylation of these 37 individuals to the DNA methylation of 38 evaluable individuals born small for gestational age. Our analysis revealed 21/37 individuals with a multi-locus methylation disturbances, characterzied by an aberrant DNA methylation in more than one imprintend gene region. Validation analyses were performed by bisulfite-pyrosequencing in the two imprinted gene regions ZDBF2 and FAM50B. Our analyses revealed each one patient previously diagnosed with Temple- and Angelman syndrome to have MLID. Furthermore, we showed that many of the aberrantly methylated imprinted gene regions in patients with MLID are not associated with the so far known typical imprinting disorders.
2016-12-31 | GSE78773 | GEO
Project description:Background and Aims: In the interleukin-10-deficient (Il10-/-) mouse model of IBD, 10 quantitative trait loci (QTL) have been shown to be associated with colitis susceptibility by linkage analyses on experimental crosses of highly susceptible C3H/HeJBir (C3Bir)-Il10-/- and partially resistant C57BL/6J (B6)-Il10-/- mice. The strongest locus (C3Bir-derived cytokine deficiency-induced colitis susceptibility [Cdcs]1 on Chromosome [Chr] 3) controlled multiple colitogenic subphenotypes and contributed the vast majority to the phenotypic variance in cecum and colon. This was demonstrated by interval-specific Chr 3 congenic mice wherein defined regions of Cdcs1 from C3Bir or B6 were bred into the IL-10-deficient reciprocal background and altered the susceptible or resistant phenotype. Furthermore, this locus likely acts by inducing innate hypo- and adaptive hyperresponsiveness, associated with impaired NFΚB responses of macrophages. The aim of the present study was to dissect the complexity of Cdcs1 by further development and characterization of reciprocal Cdcs1 congenic strains and to identify potential candidate genes in the congenic interval. Material and Methods: In total, 15 reciprocal congenic strains were generated from Il10-/- mice of either C3H/HeJBir or C57BL/6J backgrounds by 10 cycles of backcrossing. Colitis activity was monitored by histological grading. Candidate genes were identified by fine mapping of congenic intervals, sequencing, microarray analysis and a high-throughput real-time RT-PCR approach using bone marrow-derived macrophages. Results: Within the originally identified Cdcs1-interval, three independent regions were detected that likely contain susceptibility-determining genetic factors (Cdcs1.1, Cdcs1.2, and Cdcs1.3). Combining results of candidate gene approaches revealed Fcgr1, Cnn3, Larp7, and Alpk1 as highly attractive candidate genes with polymorphisms in coding or regulatory regions and expression differences between susceptible and resistant mouse strains. Conclusions: Subcongenic analysis of the major susceptibility locus Cdcs1 on mouse chromosome 3 revealed a complex genetic structure. Candidate gene approaches revealed attractive genes within the identified regions with homologs that are located in human susceptibility regions for IBD.
2009-10-01 | GSE15318 | GEO
Project description:Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus
| PRJNA914474 | ENA
Project description:Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus
| PRJNA914473 | ENA
Project description:We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families that each contain at least one affected sibling pair. The first stage, with 272 microsatellite markers and 297 families, involved a sparse map covering 23 chromosomes at intervals of approximately 15 cM. Sixteen markers that showed evidence of linkage at nominal P</=.05 were then taken through to the second stage, with an additional 184 families. This second stage confirmed evidence of linkage for markers on chromosome 11q. Additional markers from this region were then typed to create a denser map. We obtained a maximum single-point LOD score, at D11S901, of 2.40 (P=.0004) and a maximum multipoint-LOD score of 3.15, between markers D11S1358 and D11S35. A subset of 196 of the 481 families, comprising affected female sibling pairs, generated a corrected LOD score of 2.54 (P=.0003) for marker D11S901, with evidence for linkage extending 12 cM proximal to this marker. When we stratified for affected male sibling pairs there was no evidence of linkage to chromosome 11. Our data suggest that a female-specific susceptibility gene for idiopathic osteoarthritis is located on chromosome 11q.
| S-EPMC1378087 | biostudies-other
Project description:Well-defined, closed breeding populations coupled with excessive disease predispositions among purebred domestic dog breeds offer unique advantages to genetic studies of disease susceptibility. Advantages offered by canine population substructure, combined with similarity to human disease in terms of clinical presentation and response to treatment, make the dog a particularly attractive system for finding genes associated with cancer. Cancers that have been difficult to study in human families or populations are of particular interest, especially those associated with one or a small number of breeds and a high level of occurrence. Histiocytic sarcoma (HS) is a rare and poorly understood neoplasm in humans, however it occurs in 15-25% of Bernese Mountain Dogs (BMD). By combining genome-wide association studies from two geographic populations of BMD followed by fine mapping and sequencing, we have identified a cancer-associated haplotype within the MTAP/CDKN2A locus that is present in 95% of all affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in numerous complex genetic diseases including several cancers. These results demonstrate the power of studying distinctive malignancies in highly predisposed dog breeds. Here, we establish a naturally occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight regarding this cancer-associated, complex, and yet poorly understood genomic region. Genomic DNA was collected from affected and unaffected BMD in North America (NA) and Europe. Both independent and combined genome-wide association studies (GWAS) were used to identify cancer-associated loci.
2012-07-02 | E-GEOD-38011 | biostudies-arrayexpress
Project description:Multi-locus CRISPRi targeting with a single truncated guide RNA
| PRJNA1036277 | ENA