In:
Frontiers in Cardiovascular Medicine, Frontiers Media SA, Vol. 9 ( 2022-8-23)
Abstract:
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-C c.927−2A & gt;G ) or decreasing (cTnI R145W ) 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.
Type of Medium:
Online Resource
ISSN:
2297-055X
DOI:
10.3389/fcvm.2022.987889
DOI:
10.3389/fcvm.2022.987889.s001
DOI:
10.3389/fcvm.2022.987889.s002
DOI:
10.3389/fcvm.2022.987889.s003
DOI:
10.3389/fcvm.2022.987889.s004
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2022
detail.hit.zdb_id:
2781496-8
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