Transcriptional bursts and heterogeneity among cardiomyocytes in hypertrophic cardiomyopathy

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Valentin Burkart1, Kathrin Kowalski1, David Aldag-Niebling1

  • 1Institute for Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany.

Frontiers in Cardiovascular Medicine
|September 9, 2022
PubMed

Insights

Transcriptional bursting in sarcomeric genes causes cellular protein and mRNA variations in hypertrophic cardiomyopathy (HCM) patients. This allelic mosaicism contributes to contractile imbalance and disease development.

Area of Science:

  • Cardiovascular Biology
  • Molecular Genetics
  • Cellular Physiology

Background:

  • Transcriptional bursting is a prevalent gene expression mechanism.
  • Allelic expression variability arises from independent transcription of gene alleles.
  • Hypertrophic Cardiomyopathy (HCM) is linked to mutations in sarcomeric proteins.

Purpose of the Study:

  • Investigate burst-like transcription of sarcomeric genes (MYBPC3, TNNI3) in HCM.
  • Determine the consequences of this transcription mode on allelic mRNA and protein distribution.
  • Correlate transcriptional bursting with cardiac contractile function in HCM patients.

Main Methods:

  • Fluorescence in situ hybridization (RNA-FISH) to visualize gene transcription.
  • Analysis of allelic mRNA ratios in single cardiomyocytes.
  • Assessment of wildtype cMyBP-C protein distribution in cardiac tissue.
  • Measurement of calcium-dependent force generation in cardiomyocytes.

Main Results:

  • MYBPC3 and TNNI3 genes exhibit burst-like transcription in HCM patient cardiac tissue.
  • Unequal allelic ratios of TNNI3 mRNA and variable wildtype cMyBP-C protein distribution were observed.
  • Mutations caused opposing changes in calcium sensitivity, but all patients showed variable contractile force.
  • Significant contractile imbalance was evident among individual cardiomyocytes.

Conclusions:

  • Burst-like transcription of sarcomeric genes creates an allelic mosaic at mRNA and protein levels in neighboring cardiomyocytes.
  • This mosaicism is a likely contributor to the contractile imbalance observed in HCM.
  • Transcriptional bursting and subsequent allelic mosaicism are implicated in the pathogenesis of HCM.

Keywords:
burst-like transcriptioncardiomyocyte heterogeneitycell-to-cell allelic imbalancecontractile imbalancehypertrophic cardiomyopathy

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