Back to Search
Start Over
Epigenetic Analyses of Human Left Atrial Tissue Identifies Gene Networks Underlying Atrial Fibrillation
- Source :
- Circulation: Genomic and precision medicine vol.13 (2020) nr.6 p.e003085 [ISSN 2574-8300]
- Publication Year :
- 2020
-
Abstract
- BACKGROUND: Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the noncoding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes.METHODS: We generated a model of the LA noncoding genome by profiling 7 histone post-translational modifications (active: H3K4me3, H3K4me2, H3K4me1, H3K27ac, H3K36me3; repressive: H3K27me3, H3K9me3), CTCF binding, and gene expression in samples from 5 individuals without structural heart disease or AF. We used MACS2 to identify peak regions (P<0.01), applied a Markov model to classify regulatory elements, and annotated this model with matched gene expression data. We intersected chromatin states with expression quantitative trait locus, DNA methylation, and HiC chromatin interaction data from LA and left ventricle. Finally, we integrated genome-wide association data for AF and electrocardiographic traits to link disease-related variants to genes.RESULTS: Our model identified 21 epigenetic states, encompassing regulatory motifs, such as promoters, enhancers, and repressed regions. Genes were regulated by proximal chromatin states; repressive states were associated with a significant reduction in gene expression (P<2×10-16). Chromatin states were differentially methylated, promoters were less methylated than repressed regions (P<2×10-16). We identified over 15 000 LA-specific enhancers, defined by homeobox family motifs, and annotated several cardiovascular disease susceptibility loci. Intersecting AF and PR genome-wide association studies loci with long-range chromatin conformation data identified a gene interaction network dominated by NKX2-5, TBX3, ZFHX3, and SYNPO2L.CONCLUSIONS: Profiling the noncoding genome provides new insights into
Details
- Database :
- OAIster
- Journal :
- Circulation: Genomic and precision medicine vol.13 (2020) nr.6 p.e003085 [ISSN 2574-8300]
- Notes :
- DOI: 10.1161/CIRCGEN.120.003085, Circulation: Genomic and precision medicine vol.13 (2020) nr.6 p.e003085 [ISSN 2574-8300], English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1228901230
- Document Type :
- Electronic Resource