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Global chromatin landscapes identify candidate noncoding modifiers of cardiac rhythm
- Source :
- The Journal of Clinical Investigation, Vol 133, Iss 3 (2023)
- Publication Year :
- 2023
- Publisher :
- American Society for Clinical Investigation, 2023.
-
Abstract
- Comprehensive cis-regulatory landscapes are essential for accurate enhancer prediction and disease variant mapping. Although cis-regulatory element (CRE) resources exist for most tissues and organs, many rare — yet functionally important — cell types remain overlooked. Despite representing only a small fraction of the heart’s cellular biomass, the cardiac conduction system (CCS) unfailingly coordinates every life-sustaining heartbeat. To globally profile the mouse CCS cis-regulatory landscape, we genetically tagged CCS component–specific nuclei for comprehensive assay for transposase-accessible chromatin–sequencing (ATAC-Seq) analysis. Thus, we established a global CCS-enriched CRE database, referred to as CCS-ATAC, as a key resource for studying CCS-wide and component-specific regulatory functions. Using transcription factor (TF) motifs to construct CCS component–specific gene regulatory networks (GRNs), we identified and independently confirmed several specific TF sub-networks. Highlighting the functional importance of CCS-ATAC, we also validated numerous CCS-enriched enhancer elements and suggested gene targets based on CCS single–cell RNA-Seq data. Furthermore, we leveraged CCS-ATAC to improve annotation of existing human variants related to cardiac rhythm and nominated a potential enhancer-target pair that was dysregulated by a specific SNP. Collectively, our results established a CCS-regulatory compendium, identified novel CCS enhancer elements, and illuminated potential functional associations between human genomic variants and CCS component–specific CREs.
- Subjects :
- Cardiology
Medicine
Subjects
Details
- Language :
- English
- ISSN :
- 15588238
- Volume :
- 133
- Issue :
- 3
- Database :
- Directory of Open Access Journals
- Journal :
- The Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.46dde78eea664fca9e8ce2e867c261c0
- Document Type :
- article
- Full Text :
- https://doi.org/10.1172/JCI153635