Abstract
Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.5 Mb genomic region harboring multiple interacting gene promoters and enhancers. We find that this cluster and its individual components are selectively required for cardiac Scn5a expression, normal cardiac conduction and normal embryonic development. Our studies reveal physiological roles of an enhancer cluster in the SCN5A-SCN10A locus, show that it controls the chromatin architecture of the locus and Scn5a expression, and suggest that genetic variants affecting its activity may influence cardiac function.
Highlights
Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders
We found that SCN5A and SCN10A share the topologically associated domains (TADs) with EXOG, SCN11A, and WDR48 (Fig. 1a)
The activity of regulatory elements (REs) is largely limited to target genes that fall within the same TAD8, including SCN5A, SCN10A, EXOG, SCN11A, and WDR48
Summary
Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. We identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. Locusspecific and genome-wide physical proximity maps have been generated through chromosome conformation capture technologies, which has provided valuable information regarding chromatin topology and possible interactions between putative regulatory sequences and promoters[12,21,22]. These maps are mostly derived from cultured, non-cardiac cells, and most datasets are of limited resolution. RE6 contains genetic variants associated with PR interval and QRS duration[3,4,5]
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