Abstract 16742: Single-Cell Transcriptional and Epigenomic Dissection of Human Heart in Health and Coronary Artery Disease Reveals Cell-type-Specific Driver Genes and Pathways
| Autor: | Carles Boix, Manolis Kellis, Suvi Linna Kuosmanen, Eloi Schmauch, Guillermo García-Cardeña, Jarmo Gunn, Yongjin Park, Tuomas Kiviniemi, Maija Hollmén, Galani K |
|---|---|
| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Circulation. 142 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Genome-wide association studies have uncovered over 200 genetic loci underlying coronary artery disease (CAD), providing great hope for a deeper understanding of the causal mechanisms leading to this disease. However, in order to understand CAD at the molecular level, it is necessary to uncover cell-type-specific circuits and to use these circuits to dissect driver variants, genes, pathways, and cell types, in normal and diseased tissues. Here, we provide the most detailed single-cell dissection of human heart cell types, using cardiac biopsies collected during open-heart surgery from healthy, CAD, and CAD-related heart failure donors, and profiling both transcriptional (scRNA-seq) and epigenomic (scATAC-seq) changes. Using this approach, we identify 12 major heart cell types, including typical cardiovascular cells (cardiomyocytes, endothelial cells, fibroblasts), rarer cell types (B cells, neurons, Schwann cells), and previously-unrecognized layer-specific epithelial and endothelial cell types. We define markers for each cell type, providing the first extensive reference set for the living human heart. In addition, we define differential gene expression patterns in CAD relative to control samples, revealing substantial differences in cell-type-specific expression of disease-related genes, emphasizing, for example, the importance of the vascular endothelium in the pathogenesis of CAD. Strikingly, further clustering of the cell types based on specific subtypes revealed important differences in their expression patterns of disease-associated genes. These changes enrich in known CAD genetic loci, enabling us to recognize their likely target genes from scRNA-seq expression changes, candidate driver variants based on scATAC-seq localization and differential DNA accessibility, and candidate upstream regulators based on their enriched motif occurrences in scATAC loci. Overall, our results highlight the relevance and potential of single-cell transcriptional and epigenomic analyses to gain new biological insights into cardiovascular disease, and to recognize novel therapeutic target genes, pathways, and the cell types where they act. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|