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Calcium-mediated histone modifications regulate alternative splicing in cardiomyocytes

Alok Sharma1, Hieu Nguyen1, Cuiyu Geng1

  • 1Department of Genetics and Genome Sciences.

Proceedings of the National Academy of Sciences of the United States of America
|November 5, 2014
PubMed

Insights

Increased calcium levels in cardiomyocytes trigger exon skipping by altering histone modifications and RNA polymerase II elongation rates. This reveals a novel calcium-mediated splicing regulation pathway impacting gene expression.

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.
Keywords:
alternative splicingcalciumcardiomyocyteshistone hyperacetylationtranscriptional elongation rate

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