Identification of MEF2-regulated genes during muscle differentiation

Paris, James; Virtanen, Carl; Lu, Zhibin; Takahashi, Mark

doi:10.1152/physiolgenomics.00149.2004

Cited by 22 publications

(18 citation statements)

References 49 publications

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“…Using a custom CpG island array and a pan-MEF2 antibody, 20 genes were identified in C2C12 cells whose promoters were enriched for MEF2 binding (39). Of these, only nine overlapped with our microarray data and were found exclusively in the MEF2A gene set, suggesting that they may be direct targets of MEF2A.…”

Section: Discussionmentioning

confidence: 70%

MEF2 Transcription Factors Regulate Distinct Gene Programs in Mammalian Skeletal Muscle Differentiation

Estrella

Desjardins

Nocco

et al. 2015

Journal of Biological Chemistry

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Background: Myocyte enhancer factor 2 (MEF2) proteins are essential for skeletal muscle development and regeneration, but their diverse roles in differentiation have not been defined. Results: Individual MEF2 proteins regulate distinct gene programs in skeletal muscle. Conclusion: Certain genes are preferentially sensitive to a specific MEF2 isoform. Significance: These findings provide opportunities to modulate MEF2 isoform-sensitive genes in skeletal muscle health and disease.

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Section: Discussionmentioning

confidence: 70%

MEF2 Transcription Factors Regulate Distinct Gene Programs in Mammalian Skeletal Muscle Differentiation

Estrella

Desjardins

Nocco

et al. 2015

Journal of Biological Chemistry

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“…Identification and in Silico Analysis of dapr-In a previous study we combined chromatin immunoprecipitation and CpG microarray analysis to search for genes regulated by the muscle related transcription factor MEF2 during skeletal muscle differentiation (11). Using chromatin immunoprecipitation-PCR we confirmed MEF2 binding proximal to a number of genes, peaking 2 days after initiation of differentiation.…”

Section: Resultsmentioning

confidence: 90%

“…C, aliquots of each fraction were separated by gel electrophoresis and probed with antibodies to proteins located specifically to either the cytosol (␤-tubulin) or plasma membrane (Na/K ATPase). determine whether there were any novel genes through which expression was induced by MEF2 binding (11). Reconfirmation and in silico analysis led us to a previously unknown and unnamed gene, which we have called dapr.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Novel Gene, dapr, Involved in Skeletal Muscle Differentiation and Protein Kinase B Signaling

Virtanen

Paris

Takahashi

2009

Journal of Biological Chemistry

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The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been associated with a variety of cellular functions ranging from cell cycle regulation to tissue development. Although years of research have extensively characterized this signaling pathway, little is known as to how specific cellular events are coordinated by its activation. Here we demonstrate that Dapr (differentiation-associated protein), a novel protein, appears to focus one aspect of this pathway by acting as a putative scaffold protein during skeletal muscle differentiation. We present for the first time a description of this protein using in silico analysis. dapr was discovered through a previous study employing chromatin immunoprecipitation and CpG microarray analysis experiments as being regulated by myocyte-enhancing factor 2, a key transcription factor involved in the differentiation of skeletal muscle tissue. In this study we show that during the course of differentiation, Dapr binds to the PI3K signaling pathway member protein kinase B (PKB). In C 2 C 12 myoblast cells before differentiation Dapr is localized to the cytosol, migrating with PKB to the membrane after initiation of muscle differentiation. Knockdown of Dapr by RNAi resulted in inhibition of myotube formation. Our findings indicate that Dapr is a key component required by myoblasts for orchestrating their differentiation during myogenesis. Furthermore, it appears that Dapr is involved in the PI3K signaling cascade, potentially acting as a scaffold protein for PKB and coordinating its compartmentalization during differentiation. In the transformation of myoblasts into myotubes, PI3K2 signaling is one of the key pathways (1). Activation of this pathway typically begins with signaling through the activated surface receptor by insulin growth factor 1 (2). Downstream, PI3K-targeted phosphorylation produces the lipid products phosphatidylinositol 3,4-diphosphate and phosphatidylinositol 3,4,5-trisphosphate. These phosphoinositides provide membrane anchoring points for pleckstrin homology domain-containing proteins with binding motifs to them. Protein kinase B (PKB, also known as AKT) is one such protein (3). The targeted localization of PKB and other kinases to the plasma membrane is an important part of their activation (4, 5). Indeed, the compartmentalization of kinases within the cell has come to be known as a key regulatory mechanism of signaling cascades. A kinase-associated protein (6) is an example of one of the first proteins identified to function in this manner. Not only does A kinase-associated protein localize kinases to specific parts of the cell, it also brings proteins together within proximity of one another; in this case, protein phosphatase 2 and protein kinase A (7).Among its many important roles as a signal transducer, including insulin-mediated signaling, PKB has also been shown to play a pivotal role in cellular differentiation (1,8,9). Its role in the development of myotubes has been well established. Initial work demonstrated that PI3K inhibition causing ...

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“…54,55 Therefore, we measured MEF2-dependent transcription in C2C12 cells before and after serum starvation in the presence or absence of siRNA against CycT1. The interaction between endogenous MEF2 and P-TEFb was first confirmed by coimmunoprecipitation (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Positive Transcription Elongation Factor b Is an Essential Cofactor for the Activation of Transcription by Myocyte Enhancer Factor 2

Nojima

Huang

Tyagi

et al. 2008

Journal of Molecular Biology

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The positive transcription elongation factor b (P-TEFb), composed of cyclin-dependent kinase 9 and cyclin T1, stimulates the elongation of transcription by hyperphosphorylating the C-terminal region of RNA polymerase II. Aberrant activation of P-TEFb results in manifestations of cardiac hypertrophy in mice, suggesting that P-TEFb is an essential factor for cardiac myocyte function and development. Here, we present evidence that P-TEFb selectively activates transcription mediated by the myocyte enhancer factor 2 (MEF2) family of transcription factors, key regulatory factors for myocyte development. Knockdown of endogenous cyclin T1 in murine C2C12 cells abolishes MEF2-dependent reporter gene expression as well as transcription of endogenous MEF2 target genes, whereas overexpression of P-TEFb enhances MEF2-dependent transcription. P-TEFb interacts with MEF2 both in vitro and in vivo. Activation of MEF2-dependent transcription induced by serum starvation is mediated by a rapid dissociation of P-TEFb from its inhibitory subunit, HEXIM1, and a subsequent recruitment of P-TEFb to MEF2 binding sites in the promoter region of MEF2 target genes. These results indicate that recruitment of P-TEFb is a critical step for stimulation of MEF2-dependent transcription, therefore providing a fundamentally important regulatory mechanism underlying the transcriptional program in muscle cells.

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Identification of MEF2-regulated genes during muscle differentiation

Cited by 22 publications

References 49 publications

MEF2 Transcription Factors Regulate Distinct Gene Programs in Mammalian Skeletal Muscle Differentiation

MEF2 Transcription Factors Regulate Distinct Gene Programs in Mammalian Skeletal Muscle Differentiation

Identification and Characterization of a Novel Gene, dapr, Involved in Skeletal Muscle Differentiation and Protein Kinase B Signaling

The Positive Transcription Elongation Factor b Is an Essential Cofactor for the Activation of Transcription by Myocyte Enhancer Factor 2

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