Calcium-mediated histone modifications regulate alternative splicing in cardiomyocytes.

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Epigenetics

Background:

• Calcium signaling is crucial for cardiomyocyte function, regulating gene expression at the transcriptional level.
• The role of calcium in controlling alternative pre-mRNA splicing in cardiomyocytes remains largely unexplored.

Purpose of the Study:

• To investigate the impact of altered intracellular calcium levels on alternative splicing in cardiomyocytes.
• To elucidate the molecular mechanisms underlying calcium-mediated splicing regulation.

Main Methods:

• Utilized mouse primary and embryonic stem cell-derived cardiomyocytes.
• Analyzed changes in histone modifications, RNA polymerase II elongation rates, and alternative exon skipping in response to calcium level fluctuations.
• Investigated the balance between histone deacetylases and histone acetyltransferases.

Main Results:

• Increased intracellular calcium levels induced robust and reversible skipping of alternative exons in endogenous genes.
• Demonstrated a calcium-mediated mechanism involving altered histone modifications, specifically histone hyperacetylation.
• Showed that calcium affects the histone deacetylase-to-histone acetyltransferase balance, leading to increased RNA polymerase II elongation rates and subsequent exon skipping.

Conclusions:

• Calcium levels dynamically regulate alternative pre-mRNA splicing in cardiomyocytes.
• A novel mechanism links calcium signaling to epigenetic modifications (histone acetylation) and transcriptional elongation, thereby controlling alternative splicing.
• This provides new insights into how calcium transients impact cardiomyocyte gene expression output.