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Global chromatin landscapes identify candidate noncoding modifiers of cardiac rhythm

Authors :
Samadrita Bhattacharyya
Rahul K. Kollipara
Gabriela Orquera-Tornakian
Sean Goetsch
Minzhe Zhang
Cameron Perry
Boxun Li
John M. Shelton
Minoti Bhakta
Jialei Duan
Yang Xie
Guanghua Xiao
Bret M. Evers
Gary C. Hon
Ralf Kittler
Nikhil V. Munshi
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

Subjects :
Cardiology
Medicine

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