Burst-Like Transcription of Sarcomeric Genes in Hypertrophic Cardiomyopathy
Biophysical Journal(2021)SCI 2区
Hannover Med Sch | Vrije Univ Amsterdam Med Ctr | Univ Sydney
Abstract
Hypertrophic cardiomyopathy (HCM) is mostly caused by heterozygous mutations in sarcomeric genes. About 90% of mutation-positive patients encode for mutations in myosin binding protein C (cMyBP-C, MYBPC3), β-myosin heavy chain (β-MyHC, MYH7), cardiac troponin T (cTnT, TNNT2) and cardiac troponin I (cTnI, TNNI3). In previous studies, we showed a large variability in force generation between individual cardiomyocytes from HCM-patients with mutations in β-MyHC,cMyBP-C and cTnI. We hypothesized that this so-called contractile imbalance may provide a common pathomechanism how different functional effects of different mutations induce similar HCM features. Here we asked whether burst-like transcription of mutant and wildtype alleles from TNNI3 and MYBPC3 might underlie contractile imbalance as shown previously for MYH7. Using single molecule RNA-fluorescence in situ hybridization (smRNA-FISH) on tissue sections from donor controls and HCM-patients with TNNI3-mutation R145W and MYBPC3 truncation mutation c.927-2G>A, we show that burst-like transcription is a common transcriptional mechanism of TNNI3 and MYBPC3. Non-Poisson distributed TNNI3 and MYBPC3-mRNA molecules per cell support this finding. We additionally show that substantial allelic imbalance from cell to cell, as revealed by allele specific single cell RT-PCR analysis for TNNI3, is associated with this burst-like transcription. In the cMyBP-Ctrunc patient, we detected a highly variable distribution of wildtype cMyBP-C from cell to cell presumably associated with burst-like transcription. In summary, we provide evidence that at least three of the four most commonly affected genes in HCM are transcribed burst-like. The random expression of both alleles may lead to highly variable fractions of mutant per wildtype mRNA and wildtype protein from cell to cell. Due to mutation-induced alterations in contractile function this may underlie contractile imbalance between neighboring cardiomyocytes and thereby be one factor that induces hypertrophy, fibrosis and cardiomyocyte disarray in HCM patients.
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