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Epigenetic Changes Governing Scn5a Expression in Denervated Skeletal Muscle
David Carreras1,2, Rebecca Martinez-Moreno1,2, Mel Lina Pinsach-Abuin1,2
1Cardiovascular Genetics Center, Biomedical Research Institute of Girona, 17190 Salt, Spain.
International Journal of Molecular Sciences
|April 3, 2021
Summary
Denervation of rat skeletal muscle upregulates the cardiac SCN5A gene. Similar regulatory mechanisms, including Gata4 transcription factor binding and enhancer activation, are involved in both denervated muscle and cardiac tissue.
Area of Science:
- Molecular biology
- Genetics
- Cardiology
Background:
- The SCN5A gene encodes the cardiac sodium channel NaV1.5, crucial for heart rhythm.
- Genetic variants in SCN5A are linked to inherited arrhythmias.
- Mechanisms of SCN5A gene regulation are not fully understood.
Purpose of the Study:
- Investigate molecular mechanisms of SCN5A gene regulation.
- Explore SCN5A expression in denervated skeletal muscle.
- Identify conserved regulatory pathways between cardiac and skeletal muscle.
Main Methods:
- Utilized rat gastrocnemius muscle denervation model.
- Performed RNA-sequencing (RNA-seq) to analyze transcriptome changes.
- Conducted ChIP-qPCR and ChIP-seq to assess histone modifications and transcription factor binding.
- Quantified Gata4 mRNA levels.
Main Results:
- Denervation induced expression of the cardiac SCN5A isoform in skeletal muscle.
- SCN5A was among the top upregulated genes post-denervation.
- Enrichment of H3K27ac, H3K4me3, and Gata4 binding near the SCN5A promoter was observed.
- Denervation activated a cardiac SCN5A-regulating super enhancer in skeletal muscle.
Conclusions:
- Denervation stimulates cardiac SCN5A expression in skeletal muscle.
- Conserved regulatory mechanisms, including Gata4 and super enhancers, govern SCN5A expression in striated muscles.
- Suggests a shared pathway for SCN5A regulation across cardiac and skeletal muscle tissues.
