Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE266319 | GEO | 2024/07/15
REPOSITORIES: GEO
Similar Datasets
Project description:Knowledge of the locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to better understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using multiple epigenetic features in cell types from one species at a time, but such an approach can make it difficult to compare results across species. In contrast, we conducted a cross-species study defining epigenetic states and identifying cCREs in blood cell types to generate maps of the regulatory landscapes and cCREs that are comparable across species. This study used integrative modeling of eight epigenetic features jointly in both human and mouse in our Validated Systematic Integration (VISION) Project. The accuracy of the cCRE predictions was supported by orthogonal function-related data. The contribution of each epigenetic state in cCREs to gene regulation was estimated from a multivariate regression against gene expression across cell types, and these values were used to estimate an epigenetic state Regulatory Potential (esRP) score for each cCRE in each cell type. These esRP scores have broad utility for visualizing and categorizing the dynamic changes in cCREs during hematopoietic differentiation. After jointly clustering cCREs based on their esRP scores across human and mouse cell types, we found distinctive transcription factor binding motifs associated with each group of cCREs with similar patterns of regulatory activity; these associations are similar between human and mouse. Genetic variants associated with blood cell phenotypes (from the GWAS Catalog and the UK Biobank study) were highly and specifically enriched in the catalog of human VISION cCREs, indicating the utility of our cCRE predictions for understanding the impact of noncoding genetic variants on both physiologic and pathologic blood cell-related traits. The cross-species joint modeling enabled a comparison of cCREs that revealed both conserved and lineage-specific patterns of epigenetic evolution, even in the absence of genomic sequence alignment. The VISION project resources are accessible through a suite of tools and browsers at http://usevision.org.
2023-04-10 | GSE229097 | GEO
Project description:Knowledge of the locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to better understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using multiple epigenetic features in cell types from one species at a time, but such an approach can make it difficult to compare results across species. In contrast, we conducted a cross-species study defining epigenetic states and identifying cCREs in blood cell types to generate maps of the regulatory landscapes and cCREs that are comparable across species. This study used integrative modeling of eight epigenetic features jointly in both human and mouse in our Validated Systematic Integration (VISION) Project. The accuracy of the cCRE predictions was supported by orthogonal function-related data. The contribution of each epigenetic state in cCREs to gene regulation was estimated from a multivariate regression against gene expression across cell types, and these values were used to estimate an epigenetic state Regulatory Potential (esRP) score for each cCRE in each cell type. These esRP scores have broad utility for visualizing and categorizing the dynamic changes in cCREs during hematopoietic differentiation. After jointly clustering cCREs based on their esRP scores across human and mouse cell types, we found distinctive transcription factor binding motifs associated with each group of cCREs with similar patterns of regulatory activity; these associations are similar between human and mouse. Genetic variants associated with blood cell phenotypes (from the GWAS Catalog and the UK Biobank study) were highly and specifically enriched in the catalog of human VISION cCREs, indicating the utility of our cCRE predictions for understanding the impact of noncoding genetic variants on both physiologic and pathologic blood cell-related traits. The cross-species joint modeling enabled a comparison of cCREs that revealed both conserved and lineage-specific patterns of epigenetic evolution, even in the absence of genomic sequence alignment. The VISION project resources are accessible through a suite of tools and browsers at http://usevision.org.
2023-04-10 | GSE229100 | GEO
Project description:Knowledge of the locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to better understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using multiple epigenetic features in cell types from one species at a time, but such an approach can make it difficult to compare results across species. In contrast, we conducted a cross-species study defining epigenetic states and identifying cCREs in blood cell types to generate maps of the regulatory landscapes and cCREs that are comparable across species. This study used integrative modeling of eight epigenetic features jointly in both human and mouse in our Validated Systematic Integration (VISION) Project. The accuracy of the cCRE predictions was supported by orthogonal function-related data. The contribution of each epigenetic state in cCREs to gene regulation was estimated from a multivariate regression against gene expression across cell types, and these values were used to estimate an epigenetic state Regulatory Potential (esRP) score for each cCRE in each cell type. These esRP scores have broad utility for visualizing and categorizing the dynamic changes in cCREs during hematopoietic differentiation. After jointly clustering cCREs based on their esRP scores across human and mouse cell types, we found distinctive transcription factor binding motifs associated with each group of cCREs with similar patterns of regulatory activity; these associations are similar between human and mouse. Genetic variants associated with blood cell phenotypes (from the GWAS Catalog and the UK Biobank study) were highly and specifically enriched in the catalog of human VISION cCREs, indicating the utility of our cCRE predictions for understanding the impact of noncoding genetic variants on both physiologic and pathologic blood cell-related traits. The cross-species joint modeling enabled a comparison of cCREs that revealed both conserved and lineage-specific patterns of epigenetic evolution, even in the absence of genomic sequence alignment. The VISION project resources are accessible through a suite of tools and browsers at http://usevision.org.
2023-04-10 | GSE229099 | GEO
Project description:Knowledge of the locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to better understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using multiple epigenetic features in cell types from one species at a time, but such an approach can make it difficult to compare results across species. In contrast, we conducted a cross-species study defining epigenetic states and identifying cCREs in blood cell types to generate maps of the regulatory landscapes and cCREs that are comparable across species. This study used integrative modeling of eight epigenetic features jointly in both human and mouse in our Validated Systematic Integration (VISION) Project. The accuracy of the cCRE predictions was supported by orthogonal function-related data. The contribution of each epigenetic state in cCREs to gene regulation was estimated from a multivariate regression against gene expression across cell types, and these values were used to estimate an epigenetic state Regulatory Potential (esRP) score for each cCRE in each cell type. These esRP scores have broad utility for visualizing and categorizing the dynamic changes in cCREs during hematopoietic differentiation. After jointly clustering cCREs based on their esRP scores across human and mouse cell types, we found distinctive transcription factor binding motifs associated with each group of cCREs with similar patterns of regulatory activity; these associations are similar between human and mouse. Genetic variants associated with blood cell phenotypes (from the GWAS Catalog and the UK Biobank study) were highly and specifically enriched in the catalog of human VISION cCREs, indicating the utility of our cCRE predictions for understanding the impact of noncoding genetic variants on both physiologic and pathologic blood cell-related traits. The cross-species joint modeling enabled a comparison of cCREs that revealed both conserved and lineage-specific patterns of epigenetic evolution, even in the absence of genomic sequence alignment. The VISION project resources are accessible through a suite of tools and browsers at http://usevision.org.
2023-04-10 | GSE229098 | GEO
Project description:Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of morbidity and mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCRE) such as enhancers and promoters in distinct cardiac cell types has restricted the understanding of these diseases. Here, we defined >287,000 cCREs in the four chambers of the human heart at single-cell resolution, which revealed cCREs and candidate transcription factors associated with cardiac cell types in a region-dependent manner and during heart failure. We further discovered cardiovascular disease-associated genetic variants enriched within these cCREs including 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Additional functional studies revealed that two of these variants affect a cCRE controlling KCNH2/HERG expression and action potential repolarization. Overall, this comprehensive atlas of human cardiac cCREs provides the foundation for illuminating cell type-specific gene regulation in human hearts during health and disease.
2021-04-01 | GSE165837 | GEO
Project description:Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of morbidity and mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCRE) such as enhancers and promoters in distinct cardiac cell types has restricted the understanding of these diseases. Here, we defined >287,000 cCREs in the four chambers of the human heart at single-cell resolution, which revealed cCREs and candidate transcription factors associated with cardiac cell types in a region-dependent manner and during heart failure. We further discovered cardiovascular disease-associated genetic variants enriched within these cCREs including 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Additional functional studies revealed that two of these variants affect a cCRE controlling KCNH2/HERG expression and action potential repolarization. Overall, this comprehensive atlas of human cardiac cCREs provides the foundation for illuminating cell type-specific gene regulation in human hearts during health and disease.
2021-04-01 | GSE165838 | GEO
Project description:Genetic risk variants identified in genome-wide association studies (GWAS) of complex disease are primarily non-coding, and translating risk variants into mechanistic insight requires detailed gene regulatory maps in disease-relevant cell types. Here, we combined a GWAS of type 1 diabetes (T1D) in 520,580 samples with candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types defined using single nucleus ATAC-seq (snATAC-seq) of 131,554 nuclei. T1D risk variants were enriched in cCREs active in T cells and additional cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped exocrine-specific cCREs linked to genes with exocrine-specific expression. At the CFTR locus, T1D risk variant rs7795896 mapped in a ductal-specific cCRE which regulated CFTR, and the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in T1D pathogenesis and highlight the power of large-scale GWAS and single cell epigenomics for understanding the cellular origins of complex disease.
2021-03-15 | GSE163160 | GEO
Project description:Genome-wide association studies (GWAS) identified over fifty genomic loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared multiome (transcriptome and chromatin accessibility map) of 117,911 human lung cells from ever- and never-smokers to profile context-specific gene regulation. We observed that most of differentially expressed genes based on smoking status (smoking-responsive genes) were cell-type specific, and inter-cellular communication strength for Major Histocompatibility Complex-I and -II pathways were inverted between ever- and never-smokers. Accessible chromatin peak detection identified candidate cis-regulatory elements (cCREs) from each lung cell type, and 37% of them were cell-type specific. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs prioritized the variants for 68% of the GWAS loci, a subset of which was also supported by transcription factor footprinting. cCRE colocalization and single-cell based trait relevance score nominated epithelial and immune cells as the main cell groups contributing to lung cancer susceptibility. Notably, cCREs of rare epithelial cell types, including AT2-proliferating (0.13%) and basal cells (1.8%), overlapped with CCVs from multiple GWAS loci. A multi-level cCRE-gene linking system identified candidate susceptibility genes from 57% of lung cancer loci, including smoking-responsive genes. Our multiome dataset identified lung cancer susceptibility genes that were not detected in previous tissue- or cell-line-based approaches and further revealed the cell types and contexts where the susceptibility genes are functional, including the interplay of epithelial and immune cell types even in a single locus.
2024-08-14 | GSE241468 | GEO
Project description:Genome-wide association studies (GWAS) have identified over 800 loci associated with kidney function, yet the specific genes, variants, and pathways involved remain elusive. By integrating kidney function GWAS, human kidney expression and methylation quantitative trait analyses, we identified Ten-Eleven Translocation (TET) DNA demethylase 2: TET2 as a novel kidney disease risk gene. Utilizing single-cell chromatin accessibility and CRISPR-based genome editing, we highlight GWAS variants that influence TET2 expression in kidney proximal tubule cells. Experiments using kidney/tubule-specific Tet2 knockout mice indicated its protective role in cisplatin-induced acute kidney injury, as well as chronic kidney disease and fibrosis, induced by unilateral ureteral obstruction or adenine diet. Single-cell gene profiling of kidneys from Tet2 knockout mice and TET2-knock-down tubule cells revealed the altered expression of DNA damage repair and chromosome segregation genes, notably including INO80, another kidney function GWAS target gene itself. Remarkably both TET2-null and INO80-null cells exhibited an increased accumulation of micronuclei after injury, leading to the activation of cytosolic nucleotide sensor cGAS-STING. Genetic deletion of cGAS or STING in kidney tubules or pharmacological inhibition of STING protected TET2 null mice from disease development. In conclusion, our findings highlight TET2 and INO80 as key genes in the pathogenesis of kidney diseases, indicating the importance of DNA damage repair mechanisms.
2024-09-13 | GSE273027 | GEO
Project description:More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. Here we comprehensively characterize genetic associations for kidney function (n = 1,508,659 individuals), DNA methylation (n = 443 individuals) and gene expression (n = 686 individuals). We identify 878 (126 novel) kidney function associated GWAS loci and prioritize target genes for 87% of these loci using a multi-stage prioritization strategy. Heritability analysis reveal that methylation variation explains a larger fraction of GWAS heritability than gene expression. Integration of GWAS and single cell open chromatin (n = 57,229 cells) highlights the key role of proximal tubules and metabolism in kidney function regulation. Further, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits.
2022-06-16 | GSE200547 | GEO