The Experts below are selected from a list of 16284 Experts worldwide ranked by ideXlab platform
Jie Chen - One of the best experts on this subject based on the ideXlab platform.
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myocyte derived tnfsf14 is a survival factor necessary for myoblast differentiation and skeletal muscle regeneration
Cell Death and Disease, 2015Co-Authors: Rachel J Waldemerstreyer, Jie ChenAbstract:Adult skeletal muscle tissue has a uniquely robust capacity for regeneration, which gradually declines with aging or is compromised in muscle diseases. The cellular mechanisms regulating adult Myogenesis remain incompletely understood. Here we identify the cytokine tumor necrosis factor superfamily member 14 (Tnfsf14) as a positive regulator of myoblast differentiation in culture and muscle regeneration in vivo. We find that Tnfsf14, as well as its cognate receptors herpes virus entry mediator (HVEM) and lymphotoxin β receptor (LTβR), are expressed in both differentiating myocytes and regenerating myofibers. Depletion of Tnfsf14 or either receptor inhibits myoblast differentiation and promotes apoptosis. Our results also suggest that Tnfsf14 regulates Myogenesis by supporting cell survival and maintaining a sufficient pool of cells for fusion. In addition, we show that Akt mediates the survival and myogenic function of Tnfsf14. Importantly, local knockdown of Tnfsf14 is found to impair injury-induced muscle regeneration in a mouse model, affirming an important physiological role for Tnfsf14 in Myogenesis in vivo. Furthermore, we demonstrate that localized overexpression of Tnfsf14 potently enhances muscle regeneration, and that this regenerative capacity of Tnfsf14 is dependent on Akt signaling. Taken together, our findings reveal a novel regulator of skeletal Myogenesis and implicate Tnfsf14 in future therapeutic development.
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the mammalian target of rapamycin regulates c2c12 Myogenesis via a kinase independent mechanism
Journal of Biological Chemistry, 2001Co-Authors: Ebru Erbay, Jie ChenAbstract:Abstract Rapamycin inhibits differentiation of mouse C2C12 myoblasts, a tissue culture model for skeletal muscle differentiation. The mechanism by which a rapamycin-sensitive signaling pathway regulates Myogenesis is largely unknown. The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation, but its role in Myogenesis has not been examined directly. Here we report the investigation of the function of mTOR and its downstream effectors in muscle differentiation. Rapamycin exerts an inhibitory effect on C2C12 Myogenesis at different stages, implying that a rapamycin-sensitive pathway may be required for multiple processes during muscle differentiation. The mTOR protein level increases 10-fold during differentiation, via a post-transcriptional mechanism. As the first direct demonstration of the essential role of mTOR in muscle differentiation, we show that a rapamycin-resistant mTOR, but not S6 kinase 1, can rescue rapamycin-inhibited Myogenesis. Remarkably, the myogenic function of mTOR does not require its kinase activity. Two downstream effectors of the rapamycin-sensitive pathway, S6 kinase 1 and eIF4E-binding protein 1, undergo differential regulation during Myogenesis, but neither protein is the relevant effector for the myogenic signaling of mTOR. Taken together, our observations suggest a novel mTOR signaling mechanism essential for skeletal muscle differentiation.
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the mammalian target of rapamycin regulates c2c12 Myogenesis via a kinase independent mechanism
Journal of Biological Chemistry, 2001Co-Authors: Ebru Erbay, Jie ChenAbstract:Rapamycin inhibits differentiation of mouse C2C12 myoblasts, a tissue culture model for skeletal muscle differentiation. The mechanism by which a rapamycin-sensitive signaling pathway regulates Myogenesis is largely unknown. The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation, but its role in Myogenesis has not been examined directly. Here we report the investigation of the function of mTOR and its downstream effectors in muscle differentiation. Rapamycin exerts an inhibitory effect on C2C12 Myogenesis at different stages, implying that a rapamycin-sensitive pathway may be required for multiple processes during muscle differentiation. The mTOR protein level increases 10-fold during differentiation, via a post-transcriptional mechanism. As the first direct demonstration of the essential role of mTOR in muscle differentiation, we show that a rapamycin-resistant mTOR, but not S6 kinase 1, can rescue rapamycin-inhibited Myogenesis. Remarkably, the myogenic function of mTOR does not require its kinase activity. Two downstream effectors of the rapamycin-sensitive pathway, S6 kinase 1 and eIF4E-binding protein 1, undergo differential regulation during Myogenesis, but neither protein is the relevant effector for the myogenic signaling of mTOR. Taken together, our observations suggest a novel mTOR signaling mechanism essential for skeletal muscle differentiation.
Liang Zhou - One of the best experts on this subject based on the ideXlab platform.
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Linc-YY1 promotes myogenic differentiation and muscle regeneration through an interaction with the transcription factor YY1
Nature communications, 2015Co-Authors: Liang Zhou, Kun Sun, Yu Zhao, Suyang Zhang, X.m. Wang, Xiaona Chen, Fengyuan Chen, Xichen BaoAbstract:Little is known how lincRNAs are involved in skeletal Myogenesis. Here we describe the discovery of Linc-YY1 from the promoter of the transcription factor (TF) Yin Yang 1 (YY1) gene. We demonstrate that Linc-YY1 is dynamically regulated during Myogenesis in vitro and in vivo. Gain or loss of function of Linc-YY1 in C2C12 myoblasts or muscle satellite cells alters myogenic differentiation and in injured muscles has an impact on the course of regeneration. Linc-YY1 interacts with YY1 through its middle domain, to evict YY1/Polycomb repressive complex (PRC2) from target promoters, thus activating the gene expression in trans. In addition, Linc-YY1 also regulates PRC2-independent function of YY1. Finally, we identify a human Linc-YY1 orthologue with conserved function and show that many human and mouse TF genes are associated with lincRNAs that may modulate their activity. Altogether, we show that Linc-YY1 regulates skeletal Myogenesis and uncover a previously unappreciated mechanism of gene regulation by lincRNA.
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a novel target of microrna 29 ring1 and yy1 binding protein rybp negatively regulates skeletal Myogenesis
Journal of Biological Chemistry, 2012Co-Authors: Liang Zhou, Leina Lu, Peiyong Jiang, Lijun Wang, Huating WangAbstract:Abstract Skeletal muscle cell differentiation (Myogenesis) is a process orchestrated by a complex network involving transcription factors, epigenetic regulators, and microRNAs. Previous studies identified miR-29 as a pro-myogenic factor that interacts with components of Polycomb repressive complex, YY1 and Ezh2. In a genome-wide survey of miR-29-mediated transcriptome changes in C2C12 myoblasts, many epigenetic factors were found to be down-regulated by miR-29. Among them, Rybp was shown to be a direct target of miR-29 through binding to its 3′ UTR. Functional studies demonstrated that Rybp is down-regulated during Myogenesis and acts as a negative regulator of skeletal Myogenesis both in vitro during C2C12 differentiation and in vivo in injury-induced muscle regeneration. Furthermore, we found that Rybp and YY1 co-occupy several myogenic loci, including miR-29 itself, to silence their expression, thus forming a Rybp-miR-29 feedback loop. Rybp overexpression was found to enhance the enrichment of Ezh2 and trimethylation of H3K27 at target loci, suggesting it may facilitate the recruitment or stabilization of the Polycomb repressive complex. Collectively, our results identify Rybp as a novel regulator of Myogenesis that co-acts with YY1 to silence miR-29 and other myogenic loci.
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a novel target of microrna 29 ring1 and yy1 binding protein rybp negatively regulates skeletal Myogenesis
Journal of Biological Chemistry, 2012Co-Authors: Liang Zhou, Peiyong Jiang, Lijun Wang, Hao Sun, Huating WangAbstract:Background: MicroRNA-29-YY1 regulatory circuitry functions during skeletal Myogenesis. Results: A genome-wide search revealed Rybp as a novel target of miR-29, and it silences myogenic loci together with YY1. Conclusion: Rybp functions as a repressor of Myogenesis. Significance: This study identifies a novel regulatory circuitry underlying muscle formation and highlights the intimate interplay among transcription factors, epigenetic regulators, and microRNAs.
Huating Wang - One of the best experts on this subject based on the ideXlab platform.
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a novel target of microrna 29 ring1 and yy1 binding protein rybp negatively regulates skeletal Myogenesis
Journal of Biological Chemistry, 2012Co-Authors: Liang Zhou, Leina Lu, Peiyong Jiang, Lijun Wang, Huating WangAbstract:Abstract Skeletal muscle cell differentiation (Myogenesis) is a process orchestrated by a complex network involving transcription factors, epigenetic regulators, and microRNAs. Previous studies identified miR-29 as a pro-myogenic factor that interacts with components of Polycomb repressive complex, YY1 and Ezh2. In a genome-wide survey of miR-29-mediated transcriptome changes in C2C12 myoblasts, many epigenetic factors were found to be down-regulated by miR-29. Among them, Rybp was shown to be a direct target of miR-29 through binding to its 3′ UTR. Functional studies demonstrated that Rybp is down-regulated during Myogenesis and acts as a negative regulator of skeletal Myogenesis both in vitro during C2C12 differentiation and in vivo in injury-induced muscle regeneration. Furthermore, we found that Rybp and YY1 co-occupy several myogenic loci, including miR-29 itself, to silence their expression, thus forming a Rybp-miR-29 feedback loop. Rybp overexpression was found to enhance the enrichment of Ezh2 and trimethylation of H3K27 at target loci, suggesting it may facilitate the recruitment or stabilization of the Polycomb repressive complex. Collectively, our results identify Rybp as a novel regulator of Myogenesis that co-acts with YY1 to silence miR-29 and other myogenic loci.
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a novel target of microrna 29 ring1 and yy1 binding protein rybp negatively regulates skeletal Myogenesis
Journal of Biological Chemistry, 2012Co-Authors: Liang Zhou, Peiyong Jiang, Lijun Wang, Hao Sun, Huating WangAbstract:Background: MicroRNA-29-YY1 regulatory circuitry functions during skeletal Myogenesis. Results: A genome-wide search revealed Rybp as a novel target of miR-29, and it silences myogenic loci together with YY1. Conclusion: Rybp functions as a repressor of Myogenesis. Significance: This study identifies a novel regulatory circuitry underlying muscle formation and highlights the intimate interplay among transcription factors, epigenetic regulators, and microRNAs.
Stephen J Tapscott - One of the best experts on this subject based on the ideXlab platform.
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myod directly up regulates premyogenic mesoderm factors during induction of skeletal Myogenesis in stem cells
Journal of Biological Chemistry, 2011Co-Authors: Peter J Gianakopoulos, Virja Mehta, Anastassia Voronova, Yi Cao, Zizhen Yao, Josee Coutu, Xiaonan Wang, Michelle S Waddington, Stephen J TapscottAbstract:Gain- and loss-of-function experiments have illustrated that the family of myogenic regulatory factors is necessary and sufficient for the formation of skeletal muscle. Furthermore, MyoD required cellular aggregation to induce Myogenesis in P19 embryonal carcinoma stem cells. To determine the mechanism by which stem cells can be directed into skeletal muscle, a time course of P19 cell differentiation was examined in the presence and absence of exogenous MyoD. By quantitative PCR, the first MyoD up-regulated transcripts were the premyogenic mesoderm factors Meox1, Pax7, Six1, and Eya2 on day 4 of differentiation. Subsequently, the myoblast markers myogenin, MEF2C, and Myf5 were up-regulated, leading to skeletal Myogenesis. These results were corroborated by Western blot analysis, showing up-regulation of Pax3, Six1, and MEF2C proteins, prior to myogenin protein expression. To determine at what stage a dominant-negative MyoD/EnR mutant could inhibit Myogenesis, stable cell lines were created and examined. Interestingly, the premyogenic mesoderm factors, Meox1, Pax3/7, Six1, Eya2, and Foxc1, were down-regulated, and as expected, skeletal Myogenesis was abolished. Finally, to identify direct targets of MyoD in this system, chromatin immunoprecipitation experiments were performed. MyoD was observed associated with regulatory regions of Meox1, Pax3/7, Six1, Eya2, and myogenin genes. Taken together, MyoD directs stem cells into the skeletal muscle lineage by binding and activating the expression of premyogenic mesoderm genes, prior to activating myoblast genes.
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promoter specific regulation of myod binding and signal transduction cooperate to pattern gene expression
Molecular Cell, 2002Co-Authors: Stephen J Tapscott, Robert L. S. Perry, Bennett H Penn, Donald A Bergstrom, Andrew D StrandAbstract:We used expression arrays and chromatin immunoprecipitation assays to demonstrate that Myogenesis consists of discrete subprograms of gene expression regulated by MyoD. Approximately 5% of assayed genes alter expression in a specific temporal sequence, and more than 1% are regulated by MyoD without the synthesis of additional transcription factors. MyoD regulates genes expressed at different times during Myogenesis, and promoter-specific regulation of MyoD binding is a major mechanism of patterning gene expression. In addition, p38 kinase activity is necessary for the expression of a restricted subset of genes regulated by MyoD, but not for MyoD binding. The identification of distinct molecular mechanisms that regulate discrete subprograms of Myogenesis should facilitate analyses of differentiation in normal development and disease.
Alex N. Bullock - One of the best experts on this subject based on the ideXlab platform.
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small molecules dorsomorphin and ldn 193189 inhibit myostatin gdf8 signaling and promote functional myoblast differentiation
Journal of Biological Chemistry, 2015Co-Authors: Daniel Horbelt, Jan H. Boergermann, Apirat Chaikuad, I. Alfano, Eleanor Williams, Ilya Lukonin, Tobias Timmel, Alex N. BullockAbstract:GDF8, or myostatin, is a member of the TGF-β superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of Myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors. As a result, both inhibitors rescued Myogenesis in myoblasts treated with GDF8. As revealed by quantitative live cell microscopy, treatment with dorsomorphin or LDN-193189 promoted the contractile activity of myotubular networks in vitro. We therefore suggest these inhibitors as suitable tools to promote functional Myogenesis.
