Abstract
Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators and play important roles in cardiac development and congenital heart disease. In a previous study, we identified a novel lncRNA, Ppp1r1b, with expression highly correlated with myogenesis. However, the molecular mechanism that underlies Ppp1r1b-lncRNA function in myogenic regulation is unknown. By silencing Ppp1r1b-lncRNA, mouse C2C12 and human skeletal myoblasts failed to develop fully differentiated myotubes. Myogenic differentiation was also impaired in PPP1R1B-lncRNA deficient human-induced pluripotent stem cell-derived cardiomyocytes (hiPSCs-CMs). The expression of myogenic transcription factors, including MyoD, Myogenin, and Tbx5, as well as sarcomere proteins, was significantly suppressed in Ppp1r1b-lncRNA inhibited myoblast cells and neonatal mouse heart. Histone modification analysis revealed increased H3K27 tri-methylation at MyoD1 and Myogenin promoters in GapmeR treated C2C12 cells. Furthermore, Ppp1r1b-lncRNA was found to bind to Ezh2, and chromatin isolation by RNA purification (ChIRP) assay revealed enriched interaction of Ppp1r1b-lncRNA with Myod1 and Tbx5 promoters, suggesting that Ppp1r1b-lncRNA induces transcription of myogenic transcription factors by interacting with the polycomb repressive complex 2 (PRC2) at the chromatin interface. Correspondingly, the silencing of Ppp1r1b-lncRNA increased EZH2 binding at promoter regions of myogenic transcription factors. Therefore, our results suggest that Ppp1r1b-lncRNA promotes myogenic differentiation through competing for PRC2 binding with chromatin of myogenic master regulators during heart and skeletal muscle development.
Highlights
IntroductionLong noncoding RNAs (lncRNAs), which comprise the bulk of the noncoding genome, have been proven to play
Long noncoding RNAs, which comprise the bulk of the noncoding genome, have been proven to playAbbreviations: LncRNA, long noncoding RNA; ChIRP, chromatin isolation by RNA purification; PRC2, polycomb repressive complex 2; RIP, RNA immunoprecipitation; CHIP, chromatin immunoprecipitation; HiPSCs, human-induced pluripotent stem cells; sk-Fmhc, fastskeletal myosin heavy chain; congenital heart disease (CHD), congenital heart defect important roles in maintaining cardiovascular system homeostasis (Ounzain et al 2013; Touma et al 2016)
These findings revealed that Ppp1r1b-Long noncoding RNAs (lncRNAs) regulates myocyte differentiation by negatively modulating H3K27me3 of myogenic transcription factor genes via competing for PRC2 binding with chromatin
Summary
Long noncoding RNAs (lncRNAs), which comprise the bulk of the noncoding genome, have been proven to play. Skeletal and cardiac muscle both arise from myogenic mesodermal lineages and share many characteristics. Was reported that the expression patterns of cardiac and skeletal muscle transcription factors and fast-skeletal myosin heavy chain (sk-fMHC) within ventricular myocardium and skeletal muscle were similar at embryonic day (ED) 20, and the expression patterns became cardiac or skeletal muscle specific only during postnatal development (Clause et al 2012). Some types of muscular dystrophies associate with cardiomyopathy and chronic cardiac diseases (Muntoni 2003). The overlapping pattern of muscle-specific gene expression in cardiac and skeletal muscle and the common origin of cardiac and skeletal muscle pathologies suggest the existence of a common underlying regulatory scheme for the control of muscle genes expression, especially in their immature phase (Hassan et al 2014)
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