Abstract
The SCN5A gene encodes the α-subunit of the voltage-gated cardiac sodium channel (NaV1.5), a key player in cardiac action potential depolarization. Genetic variants in protein-coding regions of the human SCN5A have been largely associated with inherited cardiac arrhythmias. Increasing evidence also suggests that aberrant expression of the SCN5A gene could increase susceptibility to arrhythmogenic diseases, but the mechanisms governing SCN5A expression are not yet well understood. To gain insights into the molecular basis of SCN5A gene regulation, we used rat gastrocnemius muscle four days following denervation, a process well known to stimulate Scn5a expression. Our results show that denervation of rat skeletal muscle induces the expression of the adult cardiac Scn5a isoform. RNA-seq experiments reveal that denervation leads to significant changes in the transcriptome, with Scn5a amongst the fifty top upregulated genes. Consistent with this increase in expression, ChIP-qPCR assays show enrichment of H3K27ac and H3K4me3 and binding of the transcription factor Gata4 near the Scn5a promoter region. Also, Gata4 mRNA levels are significantly induced upon denervation. Genome-wide analysis of H3K27ac by ChIP-seq suggest that a super enhancer recently described to regulate Scn5a in cardiac tissue is activated in response to denervation. Altogether, our experiments reveal that similar mechanisms regulate the expression of Scn5a in denervated muscle and cardiac tissue, suggesting a conserved pathway for SCN5A expression among striated muscles.
Highlights
Voltage-gated sodium channels (VGSC) are key players in cell excitability
Work from Bezzina and colleagues demonstrated that certain haplotypes in the SCN5A promoter associated with changes in SCN5A transcriptional activity are linked to variations in the QRS electrocardiogram interval [29]. Another line of evidence comes from the work from van den Boogaard and colleagues, who showed that a genetic variant in a distal cis-regulatory region affecting the binding of transcription factors (TF) TBX3/TBX5 and SCN5A gene expression is associated with cardiac conduction disease [30,31]
This study reveals that the molecular mechanisms associated with re-expression of the Scn5a gene in denervated skeletal muscle resemble those that activate Scn5a transcription in cardiac tissue
Summary
Voltage-gated sodium channels (VGSC) are key players in cell excitability. The VGSC gene family is formed by nine homologous members, SCN1A–SCN11A. Work from Bezzina and colleagues demonstrated that certain haplotypes in the SCN5A promoter associated with changes in SCN5A transcriptional activity are linked to variations in the QRS electrocardiogram interval [29] Another line of evidence comes from the work from van den Boogaard and colleagues, who showed that a genetic variant in a distal cis-regulatory region affecting the binding of transcription factors (TF) TBX3/TBX5 and SCN5A gene expression is associated with cardiac conduction disease [30,31]. These findings suggest that dysregulation of SCN5A gene expression is linked to cardiac disease, and that understanding the regulatory mechanisms of SCN5A gene expression is critical to uncover novel etiologies of NaV1.5related arrhythmias. Omuecrhraesnuislmtssptrhoavtidgeoveevridnetnhceeefxoprraesusnioifineodf vSiCeNw5oAf itnhebogtehnehreaalretpaingdendeetincemrveactheadnsiksmelsettahlamt guosvcleer.n the expression of SCN5A in both heart and denervated skeletal muscle
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