Global chromatin landscapes identify candidate noncoding modifiers of cardiac rhythm.

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 ATAC-seq analysis. Thus, we established a global CCS-enriched CRE database (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 identify and independently confirm several novel TF sub-networks. Highlighting the functional importance of CCS-ATAC, we also validate numerous CCS-enriched enhancer elements and suggest gene targets based on CCS single-cell RNA-seq data. Furthermore, we leverage CCS-ATAC to improve annotation of existing human variants related to cardiac rhythm and nominate a potential enhancer-target pair dysregulated by a specific SNP. Collectively, our results establish a CCS regulatory compendium, identify novel CCS enhancer elements, and illuminate potential functional associations between human genomic variants and CCS component-specific CREs.