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Integrated Chromatin Accessibility Mapping and Expression Profiling Enables Functional Annotation of Kidney GWAS Loci

ABSTRACT: Integrated Chromatin Accessibility Mapping and Expression Profiling Enables Functional Annotation of Kidney GWAS Loci

PROVIDER: PRJNA476592 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7358310_1.fastq.gz	Fastqsanger.gz
	SRR7358310_2.fastq.gz	Fastqsanger.gz
	SRR7358320_1.fastq.gz	Fastqsanger.gz
	SRR7358320_2.fastq.gz	Fastqsanger.gz
	SRR7358330_1.fastq.gz	Fastqsanger.gz

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Integrated Chromatin Accessibility Mapping and Expression Profiling Enables Functional Annotation of Kidney GWAS Loci

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2018-06-19 | GSE115961 | GEO

Integrated Functional Genomic Analysis Enables Annotation of Kidney Genome-Wide Association Study Loci.

Project description:BackgroundLinking genetic risk loci identified by genome-wide association studies (GWAS) to their causal genes remains a major challenge. Disease-associated genetic variants are concentrated in regions containing regulatory DNA elements, such as promoters and enhancers. Although researchers have previously published DNA maps of these regulatory regions for kidney tubule cells and glomerular endothelial cells, maps for podocytes and mesangial cells have not been available.MethodsWe generated regulatory DNA maps (DNase-seq) and paired gene expression profiles (RNA-seq) from primary outgrowth cultures of human glomeruli that were composed mainly of podocytes and mesangial cells. We generated similar datasets from renal cortex cultures, to compare with those of the glomerular cultures. Because regulatory DNA elements can act on target genes across large genomic distances, we also generated a chromatin conformation map from freshly isolated human glomeruli.ResultsWe identified thousands of unique regulatory DNA elements, many located close to transcription factor genes, which the glomerular and cortex samples expressed at different levels. We found that genetic variants associated with kidney diseases (GWAS) and kidney expression quantitative trait loci were enriched in regulatory DNA regions. By combining GWAS, epigenomic, and chromatin conformation data, we functionally annotated 46 kidney disease genes.ConclusionsWe demonstrate a powerful approach to functionally connect kidney disease-/trait-associated loci to their target genes by leveraging unique regulatory DNA maps and integrated epigenomic and genetic analysis. This process can be applied to other kidney cell types and will enhance our understanding of genome regulation and its effects on gene expression in kidney disease.

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Cell-type specific meQTL extends melanoma GWAS annotation beyond eQTL and identifies a melanocyte gene regulatory network

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Implicating effector genes at COVID-19 GWAS loci using promoter-focused Capture-C in disease-relevant immune cell types [RNA-seq]

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Chromatin accessibility and gene expression during adipocyte differentiation identify context-dependent effects at cardiometabolic GWAS loci [RNA-seq]

Project description:Chromatin accessibility and gene expression in relevant cell contexts can guide identification of regulatory elements and mechanisms at genome-wide association study (GWAS) loci. To identify regulatory elements that display differential activity across adipocyte differentiation, we performed ATAC-seq and RNA-seq in a cell model of preadipocytes and adipocytes at days 4 and 14 of differentiation. For comparison, we created a consensus map of ATAC-seq peaks in 11 subcutaneous adipose tissue samples. A set of 15,919 adipocyte-dependent peaks showed stronger enrichment (60.1%) of adipocyte nuclei enhancers than 51,855 adipose tissue peaks (44.6%) or 18,244 preadipocyte-dependent peaks (11.5%). We linked context-dependent peaks to genes based on adipocyte promoter capture Hi-C data, overlap with adipose eQTL variants, and differential gene expression. Of 16,167 context-dependent peaks that could be linked to a gene, 5,184 were linked by two or more strategies to 1,675 genes. Among GWAS loci for cardiometabolic traits, adipocyte peaks showed the strongest enrichment for waist-to-hip ratio, coronary artery disease, and HDL-cholesterol, while adipose tissue peaks also showed significant enrichment for LDL-cholesterol and triglyceride levels. We identified 666 peaks linked to 507 genes by two or more methods and overlapping a GWAS signal, suggesting a regulatory mechanism at these loci. At one GWAS locus for palmitoleic acid, rs603424 was located in an adipocyte-dependent peak linked to SCD and exhibited allelic differences in transcriptional activity in adipocytes (P=0.003) but not preadipocytes (P=0.09). These results demonstrate that context-dependent peaks and genes can guide discovery of regulatory variants at GWAS loci and aid identification of regulatory mechanisms.

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