The imprinted Dlk1-Dio3 genomic region harbors a noncoding RNA cluster encoding over fifty microRNAs (miRNAs), three long noncoding RNAs (lncRNAs), and a small nucleolar RNA (snoRNA) gene array. These distinct noncoding RNAs (ncRNAs) are thought to arise from a single polycistronic transcript that is subsequently processed into individual ncRNAs, each with important roles in diverse cellular contexts. Considering these ncRNAs are derived from a polycistron, it is possible that some coordinately regulate discrete biological processes in the heart. Here, we provide a comprehensive summary of Dlk1-Dio3 miRNAs and lncRNAs, as they are currently understood in the cellular and organ-level context of the cardiovascular system. Highlighted are expression profiles, mechanistic contributions, and functional roles of these ncRNAs in heart development and disease. Notably, a number of these ncRNAs are implicated in processes often perturbed in heart disease, including proliferation, differentiation, cell death, and fibrosis. However, most literature falls short of characterizing precise mechanisms for many of these ncRNAs, warranting further investigation. Taken together, the Dlk1-Dio3 locus represents a largely unexplored noncoding regulator of cardiac homeostasis, harboring numerous ncRNAs that may serve as therapeutic targets for cardiovascular disease.
Formation of skeletal muscle is among the most striking examples of cellular plasticity in animal tissue development, and while muscle progenitor cells are reprogrammed by epithelial-mesenchymal transition (EMT) to migrate during embryonic development, the regulation of EMT in post-natal myogenesis remains poorly understood. Here, we demonstrate that the long noncoding RNA (lncRNA) Meg3 regulates EMT in myoblast differentiation and skeletal muscle regeneration. Chronic inhibition of Meg3 in C2C12 myoblasts induced EMT, and suppressed cell state transitions required for differentiation. Furthermore, adenoviral Meg3 knockdown compromised muscle regeneration, which was accompanied by abnormal mesenchymal gene expression and interstitial cell proliferation. Transcriptomic and pathway analyses of Meg3-depleted C2C12 myoblasts and injured skeletal muscle revealed a significant dysregulation of EMT-related genes, and identified TGFβ as a key upstream regulator. Importantly, inhibition of TGFβR1 and its downstream effectors, and the EMT transcription factor Snai2, restored many aspects of myogenic differentiation in Meg3-depleted myoblasts in vitro. We further demonstrate that reduction of Meg3-dependent Ezh2 activity results in epigenetic alterations associated with TGFβ activation. Thus, Meg3 regulates myoblast identity to facilitate progression into differentiation.
statement Muscle differentiation and regeneration are regulated by an evolutionarily conserved long noncoding RNA that restricts gene expression to coordinate cell state transitions Abstract Formation of skeletal muscle is among the most striking examples of cellular plasticity in animal tissue development, where mononucleated, lineage-restricted progenitor cells are reprogrammed by epithelial-mesenchymal transition (EMT) to produce multinucleated myofibers. While some mediators of EMT have been shown to function in muscle formation, the regulation of this process in this tissue remains poorly understood. The long noncoding RNA (lncRNA) Meg3 is processed from the >200 kb Dlk1-Dio3 polycistron that we have previously shown is involved in skeletal muscle differentiation and regeneration. Here, we demonstrate that Meg3 regulates EMT in myoblast differentiation and skeletal muscle regeneration. Chronic inhibition of Meg3 in C2C12 myoblasts promoted aberrant EMT activation, and suppressed cell state transitions required for fusion and myogenic differentiation. Furthermore, adenoviral Meg3 knockdown compromised muscle regeneration, which was accompanied by abnormal mesenchymal gene expression and interstitial cell proliferation in the regenerating milieu. Transcriptomic and pathway analyses of Meg3-depleted C2C12 myoblasts and injured skeletal muscle revealed a significant dysregulation of EMT-related genes, and identified TGFβ as a key upstream regulator. Importantly, chemical inhibition of TGFβR1, as well as its downstream effectors ROCK1/2 and p38 MAPK, restored many aspects of myogenic differentiation in Meg3depleted myoblasts in vitro. Thus, Meg3 regulates myoblast identity to maintain proper cell state for progression into differentiation. Benetatos L, Hatzimichael E, Londin E, Vartholomatos G, Loher P, Rigoutsos I, Briasoulis E. (2013) The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis. Cell Mol Life Sci. 70(5):795-814. Benetatos L, Vartholomatos G, Hatzimichael E (2014). DLK1-DIO3 imprinted cluster in induced pluripotency: landscape in the mist. Cell Mol Life Sci. 71(22):4421-30. Buckingham M, Rigby PW (2014). Gene regulatory networks and transcriptional mechanisms that control myogenesis. Dev Cell. 28(3):225-38. Burks TN, Cohn RD. (2011) Role of TGF-β signaling in inherited and acquired myopathies. Skelet Muscle. 1(1):19. Campbell K, Casanova J. (2016) A common framework for EMT and collective cell migration. Development. 143(23):4291-4300. Caretti G, Di Padova M, Micales B, Lyons GE, Sartorelli V. (2004) The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev. 18(21):2627-38. Castel D, Baghdadi MB, Mella S, Gayraud-Morel B, Marty V, Cavaillé J, Antoniewski C, Tajbakhsh S (2018). Small-RNA sequencing identifies dynamic microRNA deregulation during skeletal muscle lineage progression. Sci Rep. 8(1):4208. Chal J, Pourquié O (2017). Making muscle: skeletal myogenesis in vivo and in vitro. . (2018). MEG3 affects the pro...
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