Global discovery of SLE genetic risk variant allelic enhancer activity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA601725 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10902989_1.fastq.gz | Fastqsanger.gz | |||
| SRR10902989_2.fastq.gz | Fastqsanger.gz | |||
| SRR10902990.fastq.gz | Fastqsanger.gz | |||
| SRR10902991.fastq.gz | Fastqsanger.gz | |||
| SRR10902992.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 26 |
Similar Datasets
Project description:Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3,073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we constructed a massively parallel reporter assays (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into Epstein-Barr virus-transformed B cell line GM12878 revealed 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. Combined with allelic enhancer activity analyses in Jurkat cell line, we identified shared and unique allelic transcriptional regulatory mechanisms at SLE risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around 51 allelic variants identified one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second, larger class of TFs that also bind allelically but do not have their motifs directly altered by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE.
2021-01-31 | GSE143792 | GEO
Project description:The IRF5-SLE risk haplotype is associated with SLE disease severity. We hypothesized that neutrophils from healthy risk donors would carry a pathogenic gene signature compared to non-risk donors. To compare basal neutrophil gene signature between risk and non-risk healthy individuals, fresh whole blood was collected from healthy donors, and granulocytes were extracted from the remaining pellet following Ficoll purification. RNA-seq libraries were prepared from globin-reduced RNA extracted from the granulocytes using the Qiagen RNA preparation kit.
2020-04-07 | GSE137067 | GEO
Project description:Our fine-mapping of 76 non-MHC loci associated with risk for rheumatoid arthritis (RA, 11,475 cases, 15,870 controls) has recently identified rs117701653, a non-coding single nucleotide polymorphism (SNP) in the CTLA4/CD28/ICOS locus, as the variant most likely to modulate RA risk within this region, with the minor allele (C) showing disease protection compared to the major allele (A). Notably, this SNP exhibits allele-specific protein binding, further supporting its regulatory nature, including greater binding of proteins from Jurkat T cell nuclear extract to the protective allele (C) than to the risk allele (A) by electrophoretic mobility shift assay (EMSA). To identify this protein or protein complex, we applied an efficient DNA pulldown technique, flanking restriction enhanced pulldown (FREP), using nuclear extract from Jurkat T cells, bait DNA corresponding to the (C) allele of rs117701653, competitor DNA fragment, and irrelevant DNA sequence as a negative control. Mass spectrometry analysis of peptides released from FREP identified 43 proteins. Our strongest candidate was structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1), which exhibited specific binding to the (C) allele of rs117701653. We confirmed the allelic affinity of SMCHD1 using multiple orthogonal approaches, including FREP and western blotting, EMSA with anti-SMCHD1 antibodies, and CHIP-qPCR with CRISPR-modified Jurkat clones bearing different genotype at rs117701653. In this study, we identified SMCHD1, a chromatin regulator that binds allelically to the rs117701653 allele (C) associated with protection against RA risk.
2024-05-23 | PXD048977 | Pride
Project description:Integrative discovery of treatments for high-risk neuroblastoma
| PRJNA495016 | ENA
Project description:Genome-wide association studies (GWAS) have identified twenty melanoma susceptibility loci. To identify susceptibility genes and variants simultaneously from multiple GWAS loci, we integrated massively-parallel reporter assays (MPRA) with melanocyte-specific expression quantitative trait locus (eQTL) profiling. We identified thirty-nine candidate functional variants displaying allelic transcriptional activity, of which nine from four loci were also correlated with local gene expression in melanocytes (CTSS, CASP8, MX2, and MAFF). Among these, we further characterized the locus in MX2 gene on chromosome band Chr21q22.3 and validated a functional variant, rs398206. The functional variant mediates allelic transcriptional activity via binding of the transcription factor, YY1. This allelic transcriptional regulation largely accounts for a significant cis-eQTL of the HIV-1 restriction gene, MX2, in primary melanocytes, where the melanoma risk-associated A allele is correlated with higher MX2 levels. Melanocyte-specific transgenic expression of human MX2 in a zebrafish model demonstrated an accelerated melanoma formation in a BRAFV600E background. Thus, using an efficient scalable approach to streamline GWAS follow-up functional studies, we uncovered a pleiotropic function of MX2 in melanoma susceptibility.
2020-04-23 | GSE149161 | GEO
Project description:Genome-wide association studies (GWAS) have identified twenty melanoma susceptibility loci. To identify susceptibility genes and variants simultaneously from multiple GWAS loci, we integrated massively-parallel reporter assays (MPRA) with melanocyte-specific expression quantitative trait locus (eQTL) profiling. We identified thirty-nine candidate functional variants displaying allelic transcriptional activity, of which nine from four loci were also correlated with local gene expression in melanocytes (CTSS, CASP8, MX2, and MAFF). Among these, we further characterized the locus in MX2 gene on chromosome band Chr21q22.3 and validated a functional variant, rs398206. The functional variant mediates allelic transcriptional activity via binding of the transcription factor, YY1. This allelic transcriptional regulation largely accounts for a significant cis-eQTL of the HIV-1 restriction gene, MX2, in primary melanocytes, where the melanoma risk-associated A allele is correlated with higher MX2 levels. Melanocyte-specific transgenic expression of human MX2 in a zebrafish model demonstrated an accelerated melanoma formation in a BRAFV600E background. Thus, using an efficient scalable approach to streamline GWAS follow-up functional studies, we uncovered a pleiotropic function of MX2 in melanoma susceptibility.
2020-04-20 | GSE129237 | GEO
Project description:Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we construct a massively parallel reporter assay (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into the Epstein-Barr virus-transformed B cell line GM12878 reveals 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. Comparison of MPRA results in GM12878 and Jurkat T cell lines highlights shared and unique allelic transcriptional regulatory mechanisms at SLE risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around allelic variants identifies one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second class of TFs that bind allelically without direct alteration of their motif by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE.
| S-EPMC7955039 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified twenty melanoma susceptibility loci. To identify susceptibility genes and variants simultaneously from multiple GWAS loci, we integrated massively-parallel reporter assays (MPRA) with melanocyte-specific expression quantitative trait locus (eQTL) profiling. We identified thirty-nine candidate functional variants displaying allelic transcriptional activity, of which nine from four loci were also correlated with local gene expression in melanocytes (CTSS, CASP8, MX2, and MAFF). Among these, we further characterized the locus in MX2 gene on chromosome band Chr21q22.3 and validated a functional variant, rs398206. The functional variant mediates allelic transcriptional activity via binding of the transcription factor, YY1. This allelic transcriptional regulation largely accounts for a significant cis-eQTL of the HIV-1 restriction gene, MX2, in primary melanocytes, where the melanoma risk-associated A allele is correlated with higher MX2 levels. Melanocyte-specific transgenic expression of human MX2 in a zebrafish model demonstrated an accelerated melanoma formation in a BRAFV600E background. Thus, using an efficient scalable approach to streamline GWAS follow-up functional studies, we uncovered a pleiotropic function of MX2 in melanoma susceptibility.
2020-04-20 | GSE129242 | GEO
Project description:Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE) and significantly contributes to morbidity and mortality. To date, no pharmacologic intervention has shown to reduce CV risk in SLE. Dysregulation of innate immune responses, including aberrant type I-Interferon (IFN)-neutrophil interactions, has been proposed to significantly contribute to enhanced CV risk in SLE. In lupus animal models, the Janus kinase/signal transducers and activators of transcription (JAK/STAT) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We hypothesized that JAK/STAT inhibition in SLE subjects would result in amelioration of cardiometabolic and immunologic parameters previously associated with enhanced CVD risk.
2021-03-01 | GSE139940 | GEO