Transcriptional bursts and heterogeneity among cardiomyocytes in hypertrophic cardiomyopathy

Burkart, Valentin and Kowalski, Kathrin and Aldag-Niebling, David and Beck, Julia and Frick, Dirk Alexander and Holler, Tim and Radocaj, Ante and Piep, Birgit and Zeug, Andre and Hilfiker-Kleiner, Denise and dos Remedios, Cristobal G. and van der Velden, Jolanda and Montag, Judith and Kraft, Theresia (2022) Transcriptional bursts and heterogeneity among cardiomyocytes in hypertrophic cardiomyopathy. Frontiers in Cardiovascular Medicine, 9. ISSN 2297-055X

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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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 01 Mar 2023 01:05
Last Modified: 01 Mar 2023 01:05

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