Ppp1r1b-lncRNA inhibits PRC2 at myogenic regulatory genes to promote cardiac and skeletal muscle development in mouse and human

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.

lncRNA FDNCR promotes apoptosis of granulosa cells by targeting the miR-543-3p/DCN/TGF-β signaling pathway in Hu sheep

“…At the post-transcriptional level, lncRNA can serve as efficient microRNA (miRNA) sponges—termed competing endogenous RNAs (ceRNAs)—that interact with miRNA to regulate gene expression. 6 Recently, numerous lncRNAs have been identified in humans and other organisms that play diverse roles in regulating various phenomenon, such as cell proliferation and apoptosis, 7 , 8 cell development, 9 cell differentiation, 10 and development of certain diseases. 11 , 12 Specifically, lncRNAs are involved in regulating spermatogenesis, 13 , 14 steroidogenesis, 15 embryo implantation 16 and development, 17 follicular development, 18 oocyte maturation, 19 GC apoptosis and proliferation, 20 , 21 and reproductive diseases, 22 , 23 suggesting their importance in reproduction.…”

Expression Profile of Long Noncoding RNAs and Circular RNAs in Mouse C3H10T1/2 Mesenchymal Stem Cells Undergoing Myogenic and Cardiomyogenic Differentiation

“…Myogenic and specification and differentiation of the heart are complex biological processes determined by the activities of gene regulatory networks. At the molecular level, emerging studies have confirmed the role of long noncoding RNAs (lncRNAs) in controlling major biological processes that affect stem cell differentiation and development [ 10 , 11 ]. For instance, it was shown that lncRNA Fendrr and Braveheart ( Bvht ) is essential for proper fate control of lateral mesoderm derivatives [ 12 ].…”

Long Non-Coding RNAs (lncRNAs) in Cardiovascular Disease Complication of Type 2 Diabetes

“…As for cardiac development, Braveheart (BVHT) lncRNA was the first lncRNA found to be necessary for the activation of important cardiac genes and transcription factors for cardiogenic differentiation and development [ 161 , 162 ]. Following that, many studies have identified other lncRNAs such as Fendrr [ 163 ], Linc1405 [ 164 ], HoxBlinc RNA [ 165 ], Handsdown ( Hdn ) [ 166 ] in mice, and (CAR)diac (M)esoderm (E)nhancer-associated (N)on-coding RNA ( CARMEN ) [ 167 ], Heart Brake LncRNA 1 ( HBL1 ) [ 168 ] and Ppp1r1b [ 169 ] in human. The majority of these lncRNAs interact with Polycomb repressive complex-2 (PRC2), a histone methyltransferase responsible for epigenetic silencing during the development of the heart and body wall [ 170 ].…”