TY - JOUR
T1 - Transcriptional bursts and heterogeneity among cardiomyocytes in hypertrophic cardiomyopathy
AU - Burkart, Valentin
AU - Kowalski, Kathrin
AU - Aldag-Niebling, David
AU - Beck, Julia
AU - Frick, Dirk Alexander
AU - Holler, Tim
AU - Radocaj, Ante
AU - Piep, Birgit
AU - Zeug, Andre
AU - Hilfiker-Kleiner, Denise
AU - dos Remedios, Cristobal G.
AU - van der Velden, Jolanda
AU - Montag, Judith
AU - Kraft, Theresia
N1 - Funding Information:
This work was supported by the Deutsche Forschungsgemeinschaft [grant number KR1187/22-1 to TK] and the European Research Area Network on Cardiovascular Disease [grant “SCALE”, BMBF Number 01KL2007 to JM].
Funding Information:
The authors thank Torsten Beier, and Alexander Lingk, Molecular and Cell Physiology, Hannover Medical School, for excellent technical assistance and Britta Keyser, formerly Department of Human Genetics, Hannover Medical School for sequence analysis of HCM-genes in patients and donors.
Publisher Copyright:
Copyright © 2022 Burkart, Kowalski, Aldag-Niebling, Beck, Frick, Holler, Radocaj, Piep, Zeug, Hilfiker-Kleiner, dos Remedios, van der Velden, Montag and Kraft.
PY - 2022/8/23
Y1 - 2022/8/23
N2 - 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.
AB - 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.
KW - burst-like transcription
KW - cardiomyocyte heterogeneity
KW - cell-to-cell allelic imbalance
KW - contractile imbalance
KW - hypertrophic cardiomyopathy
UR - https://www.scopus.com/pages/publications/85137987795
U2 - 10.3389/fcvm.2022.987889
DO - 10.3389/fcvm.2022.987889
M3 - Article
C2 - 36082122
SN - 2297-055X
VL - 9
JO - Frontiers in cardiovascular medicine
JF - Frontiers in cardiovascular medicine
M1 - 987889
ER -