Frontiers in Cardiovascular Medicine (Aug 2022)

Transcriptional bursts and heterogeneity among cardiomyocytes in hypertrophic cardiomyopathy

  • Valentin Burkart,
  • Kathrin Kowalski,
  • David Aldag-Niebling,
  • Julia Beck,
  • Dirk Alexander Frick,
  • Tim Holler,
  • Ante Radocaj,
  • Birgit Piep,
  • Andre Zeug,
  • Denise Hilfiker-Kleiner,
  • Cristobal G. dos Remedios,
  • Jolanda van der Velden,
  • Judith Montag,
  • Theresia Kraft

DOI
https://doi.org/10.3389/fcvm.2022.987889
Journal volume & issue
Vol. 9

Abstract

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Transcriptional bursting is a common expression mode for most genes where independent transcription of alleles leads to different ratios of allelic mRNA from cell to cell. Here we investigated burst-like transcription and its consequences in cardiac tissue from Hypertrophic Cardiomyopathy (HCM) patients with heterozygous mutations in the sarcomeric proteins cardiac myosin binding protein C (cMyBP-C, MYBPC3) and cardiac troponin I (cTnI, TNNI3). Using fluorescence in situ hybridization (RNA-FISH) we found that both, MYBPC3 and TNNI3 are transcribed burst-like. Along with that, we show unequal allelic ratios of TNNI3-mRNA among single cardiomyocytes and unequally distributed wildtype cMyBP-C protein across tissue sections from heterozygous HCM-patients. The mutations led to opposing functional alterations, namely increasing (cMyBP-Cc.927−2A>G) or decreasing (cTnIR145W) calcium sensitivity. Regardless, all patients revealed highly variable calcium-dependent force generation between individual cardiomyocytes, indicating contractile imbalance, which appears widespread in HCM-patients. Altogether, we provide strong evidence that burst-like transcription of sarcomeric genes can lead to an allelic mosaic among neighboring cardiomyocytes at mRNA and protein level. In HCM-patients, this presumably induces the observed contractile imbalance among individual cardiomyocytes and promotes HCM-development.

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