Cardiac cell type-specific gene regulatory programs and disease risk association
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ABSTRACT:
PROVIDER: PRJNA698224 | ENA |
REPOSITORIES: ENA
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Project description:Cardiac cell type-specific gene regulatory programs and disease risk association [RNA-seq]
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Project description:Cardiac cell type-specific gene regulatory programs and disease risk association [ATAC-seq]
| PRJNA698273 | ENA
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: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:This SuperSeries is composed of the SubSeries listed below.
2021-04-01 | GSE165839 | GEO
Project description:Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCREs) 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 found 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 atlas of human cardiac cCREs provides the foundation for illuminating cell type-specific gene regulation in human hearts during health and disease.
| S-EPMC8121433 | biostudies-literature
Project description:Genome-Wide Association Study of Lung Cancer Risk
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Project description:Age-dependent Lamin remodeling induces cardiac dysfunction via dysregulation of cardiac transcriptional programs
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Project description:Alternative splicing is critical for development. However, its role in the specification of the three embryonic germ layers is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage. The most prominent splicing program differences are observed between definitive endoderm and cardiac mesoderm. Integrative multi-omics analyses link each program with lineage-specific RNA binding protein regulators, and further suggest a widespread role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI disrupts the cardiac mesoderm-associated alternative splicing program and formation of myocytes. These changes likely arise in part through reduced expression of BIN1 splice variants linked to cardiac development. Collectively, our results thus uncover alternative splicing programs associated with the three germ lineages and demonstrate an important role for QKI in the formation of cardiac mesoderm.
2022-02-01 | MSV000088762 | MassIVE
Project description:Genome-wide association studies (GWAS) have discovered thousands of risk loci for common, complex diseases, each of which could point to genes and gene programs that influence disease. For some diseases, it has been observed that GWAS signals converge on a smaller number of biological programs, and that this convergence can help to identify causal genes. However, identifying such convergence remains challenging: each GWAS locus can have 2-20 candidate genes, the cellular programs a gene participates in are difficult to define in an unbiased fashion, and it remains unclear which genes and programs would be likely to influence disease risk. Here, we explored a new approach to address this challenge, by creating an unbiased catalog of gene programs and their regulators in endothelial cells to link variants to functions for coronary artery disease (CAD). To do so, we applied CRISPRi-Perturb-seq to knock down all expressed genes within 500 Kb of all CAD GWAS loci (2,285 genes in total) and measure their effects on the transcriptome using single-cell RNA-seq. We used consensus non-negative matrix factorization to define 60 gene expression programs—including core cellular programs, such as ribosome biogenesis, and endothelial cell-specific programs, such as flow response and angiogenesis—and link these programs to upstream regulators including transcription factors, chromatin regulators, metabolic enzymes, and signaling cascades. By combining this gene-to-program catalog with variant-to-gene maps, we find that candidate CAD genes converge onto 6 interrelated gene programs, together involving known and novel genes in 39 of 229 CAD GWAS loci. Analysis of these programs revealed that the cerebral cavernous malformations (CCM) complex—whose potential connection to CAD has not been previously explored—acts upstream to regulate other CAD genes involved in cytoskeletal organization, extracellular matrix remodeling, and cell migration. The strongest regulator of these programs is TLNRD1, a highly conserved but poorly studied gene that we show acts in the CCM pathway and regulates actin organization and endothelial cell barrier function. Together, our study nominates new genes that likely influence risk for CAD, identifies convergence of CAD risk loci into certain gene programs in endothelial cells, and demonstrates a generalizable strategy to catalog gene programs to connect disease variants to functions.
2022-11-01 | GSE210522 | GEO