Gene expression and H3K27ac changes upon Rat gastrognemius muscle denervation. Denervation

The SCN5A gene encodes the alpha-subunit of the voltage-gated cardiac sodium channel(Na V 1.5), 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 of SCN5A gene regulation are not yet well understood. To understand the molecular basis of SCN5A expression, we used rat gastrocnemius muscle four days following denervation, a process known to promote the expression of SCN5A in skeletal muscle. Our results show that denervation induces the expression of the adult Scn5a isoform. RNA-seq analysis showed that Scn5a is among the 50 top upregulated genes in response to denervation. Consistent with this increase in expression, ChIP-qPCR showed enrichment of H3K27ac and H3K4me3 near the Scn5a promoter region and binding of the transcription factor Gata4. Notably, Gata4 expression is also significantly induced upon denervation. Genome-wide analysis of H3K27ac by ChIP-seq showed activation of a super enhancer recently described to regulate Scn5a in cardiac tissue. 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.