Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During skeletal myogenesis, muscle-regulatory factors bHLH and MEF2 promote the expression of muscle-specific genes by recruiting several chromatin-modifying complexes on specific DNA regulatory sequences. A number of MyoD-interacting proteins have been reported, but whether they are recruited to the chromatin of myogenic loci, and the relationship with other chromatin bound proteins is unknown. We show that MyoD recruits cdk9/cyclin T2, together with the histone acetyltransferases p300 and PCAF, and the chromatin remodeling complex SWI/SNF, on promoters and enhancers of muscle-specific genes, and that this event correlates with the acetylation of histone tails, remodeling of chromatin, and phosphorylation of the C-terminal domain (CTD) of the RNA polymerase II at these elements.
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PMID:MyoD recruits the cdk9/cyclin T2 complex on myogenic-genes regulatory regions. 1624 9

Positive transcription elongation factor b (P-TEFb) phosphorylates the C-terminal domain of RNA polymerase II, facilitating transcriptional elongation. In addition to its participation in general transcription, P-TEFb is recruited to specific promoters by some transcription factors such as c-Myc or MyoD. The P-TEFb complex is composed of a cyclin-dependent kinase (cdk9) subunit and a regulatory partner (cyclin T1, cyclin T2, or cyclin K). Because cdk9 has been shown to participate in differentiation processes, such as muscle cell differentiation, we studied a possible role of cdk9 in adipogenesis. In this study we show that the expression of the cdk9 p55 isoform is highly regulated during 3T3-L1 adipocyte differentiation at RNA and protein levels. Furthermore, cdk9, as well as cyclin T1 and cyclin T2, shows differences in nuclear localization at distinct stages of adipogenesis. Overexpression of cdk9 increases the adipogenic potential of 3T3-L1 cells, whereas inhibition of cdk9 by specific cdk inhibitors, and dominant-negative cdk9 mutant impairs adipogenesis. We show that the positive effects of cdk9 on the differentiation of 3T3-L1 cells are mediated by a direct interaction with and phosphorylation of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master regulator of this process, on the promoter of PPARgamma target genes. PPARgamma-cdk9 interaction results in increased transcriptional activity of PPARgamma and therefore increased adipogenesis.
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PMID:Peroxisome proliferator-activated receptor gamma recruits the positive transcription elongation factor b complex to activate transcription and promote adipogenesis. 1648 39

MyoD regulates skeletal myogenesis. Since proteins associated with MyoD exert regulatory functions, their identification is expected to contribute important insights into the mechanisms governing gene expression in skeletal muscle. We have found that the RNA helicases p68/p72 are MyoD-associated proteins and that the noncoding RNA SRA also immunoprecipitates with MyoD. In vitro and in vivo experiments indicated that both p68/p72 and SRA are coactivators of MyoD. RNA interference toward either p68/p72 or SRA prevented proper activation of muscle gene expression and cell differentiation. Unexpectedly, reducing the levels of p68/p72 proteins impaired recruitment of the TATA binding protein TBP; RNA polymerase II; and the catalytic subunit of the ATPase SWI/SNF complex, Brg-1, and hindered chromatin remodeling. These findings reveal that p68/p72 play a critical role in promoting the assembly of proteins required for the formation of the transcription initiation complex and chromatin remodeling.
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PMID:The RNA helicases p68/p72 and the noncoding RNA SRA are coregulators of MyoD and skeletal muscle differentiation. 1701 93

MyoD is sufficient to initiate the skeletal muscle gene expression program. Transcription of certain MyoD target genes occurs in the early phases, whereas that of others is induced only at later stages, although MyoD is present throughout the differentiation process. MyoD acetylation regulates transcriptional competency, yet whether this post-translational modification is equally relevant for activation of all the MyoD targets is unknown. Moreover, the molecular mechanisms through which acetylation ensures that MyoD achieves its optimal activity remain unexplored. To address these two outstanding issues, we have coupled genome-wide expression profiling and chromatin immunoprecipitation in a model system in which MyoD or its nonacetylatable version was inducibly activated in mouse embryonic fibroblasts derived from MyoD(-/-)/Myf5(-/-) mice. Our results reveal that MyoD acetylation influences transcription of selected genes expressed at defined stages of the muscle program by regulating chromatin access of MyoD, histone acetylation, and RNA polymerase II recruitment.
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PMID:MyoD acetylation influences temporal patterns of skeletal muscle gene expression. 1796 12

Adult skeletal muscle contains a specialized population of myogenic quiescent stem cells, termed satellite cells, which contribute to repair myofibers after injury. During muscle regeneration, satellite cells exit their normal quiescent state, proliferate, activating MyoD and Myf-5 expression, and finally differentiate and fuse to reconstitute the injured muscle architecture. We have previously reported that cdk9 is required for myogenesis in vitro by activating MyoD-dependent transcription. In myoblasts induced to differentiate, MyoD recruits cdk9 on the chromatin of muscle-specific regulatory regions. This event correlates with chromatin-modifying enzyme recruitment and phosphorylation of cdk9-specific target residues at the carboxyl-terminal domain of RNA polymerase II. Here we report that a second cdk9 isoform, termed cdk9-55, plays a fundamental role in muscle regeneration and differentiation in vivo. This alternative form is specifically induced in injured myofibers and its activity is strictly required for the completion of muscle regeneration process.
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PMID:Cdk9-55: a new player in muscle regeneration. 1854 1

Incorporation of circulating hematopoietic progenitor cells (HPCs) into damaged skeletal muscle has been proposed as a novel mechanism of tissue repair complementary to satellite cell-dependent regeneration. We studied the occurrence and myoendothelial differentiation of HPCs in muscle of patients with inflammatory myopathies. Muscle biopsies from untreated patients with dermatomyositis, polymyositis, inclusion body myositis, and controls were investigated for the expression of endothelial (CD31, von Willebrand factor, vascular endothelial growth factor receptor 2), hematopoietic (CD34, CD133, CD45), and myogenic (Pax7, MyoD) markers by immunohistochemistry and reverse-transcriptase-polymerase chain reaction. Confocal laser scanning microscopy was used to visualize coexpression of CD34, CD133, von Willebrand factor, or Pax7 on individual cells. Morphometric analysis revealed significantly increased numbers of CD133 cells per square millimeter in polymyositis and inclusion body myositis compared with controls (p < 0.001); this correlated with the density of CD45 infiltrates (p < 0.001). By confocal laser scanning microscopy, we detected several mononuclear cells that coexpressed either CD34/von Willebrand factor or CD133/Pax7 with or without CD34 reactivity, indicating endothelial or myogenic commitment of some HPCs in skeletal muscle. Rarely, CD133/CD34/Pax7 cells seemed to occupy satellite cell niches or to incorporate into preexisting myofibers. Our findings suggest that circulating HPCs colonize skeletal muscle in inflammatory conditions and provide evidence for in situ myoendothelial differentiation of some of these cells.
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PMID:Endothelial and myogenic differentiation of hematopoietic progenitor cells in inflammatory myopathies. 1859 42

Although FoxO and Pax proteins represent two important families of transcription factors in determining cell fate, they had not been functionally or physically linked together in mediating regulation of a common target gene during normal cellular transcription programs. Here, we identify MyoD, a key regulator of myogenesis, as a direct target of FoxO3 and Pax3/7 in myoblasts. Our cell-based assays and in vitro studies reveal a tight codependent partnership between FoxO3 and Pax3/7 to coordinately recruit RNA polymerase II and form a preinitiation complex (PIC) to activate MyoD transcription in myoblasts. The role of FoxO3 in regulating muscle differentiation is confirmed in vivo by observed defects in muscle regeneration caused by MyoD downregulation in FoxO3 null mice. These data establish a mutual interdependence and functional link between two families of transcription activators serving as potential signaling sensors and regulators of cell fate commitment in directing tissue specific MyoD transcription.
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PMID:Codependent activators direct myoblast-specific MyoD transcription. 1885 38

Rhabdomyosarcoma (RMS) is the commonest soft-tissue sarcoma in childhood and is characterized by expression of myogenic proteins, including the transcription factors MyoD and myogenin. There are two main subgroups, embryonal RMS and alveolar RMS (ARMS). Most ARMS are associated with chromosomal translocations that have breakpoints in introns of either PAX3 or PAX7, and FOXO1A. These translocations create chimeric transcription factors termed PAX3/FOXO1A and PAX7/FOXO1A respectively. Upon ectopic PAX3/FOXO1A expression, together with other genetic manipulation in mice, both differentiating myoblasts and satellite cells (the resident stem cells of postnatal muscle) can give rise to tumours with ARMS characteristics. As PAX3 and PAX7 are part of transcriptional networks that regulate muscle stem cell function in utero and during early postnatal life, PAX3/FOXO1A and PAX7/FOXO1A may subvert normal PAX3 and PAX7 functions. Here we examined how PAX3/FOXO1A and PAX7/FOXO1A affect myogenesis in satellite cells. PAX3/FOXO1A or PAX7/FOXO1A inhibited myogenin expression and prevented terminal differentiation in murine satellite cells: the same effect as dominant-negative (DN) Pax3 or Pax7 constructs. The transcription of MyoD-target genes myogenin and muscle creatine kinase were suppressed by PAX3/FOXO1A or PAX7/FOXO1A in C2C12 myogenic cells again as seen with Pax3/7DN. PAX3/FOXO1A or PAX7/FOXO1A did not inhibit the transcriptional activity of MyoD by perturbing MyoD expression, localization, phosphorylation or interaction with E-proteins. Chromatin immunoprecipitation on the myogenin promoter showed that PAX3/FOXO1A or PAX7/FOXO1A did not prevent MyoD from binding. However, PAX3/FOXO1A or PAX7/FOXO1A reduced occupation of the myogenin promoter by RNA polymerase II and decreased acetylation of histone H4, but did not directly bind to the myogenin promoter. Together, these observations reveal that PAX3/FOXO1A and PAX7/FOXO1A act to prevent myogenic differentiation via suppression of the transcriptional activation of MyoD-target genes.
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PMID:Alveolar rhabdomyosarcoma-associated proteins PAX3/FOXO1A and PAX7/FOXO1A suppress the transcriptional activity of MyoD-target genes in muscle stem cells. 2271 Jul 12

Cyclin-dependent kinase 9 (Cdk9) is a serine-threonine kinase, involved in many cellular processes. The regulatory units of Cdk9 are the T family Cyclins (T1, T2) and Cyclin K. Cyclin T2 has two forms termed Cyclin T2a and Cyclin T2b that arise by an alternative splicing of the primary transcript. Upon induction of muscle differentiation, MyoD recruits Cdk9/Cyclin T2 on muscle-specific gene promoter sequences. This complex is able to phosphorylate the C-terminal domain of RNA polymerase II, enhancing MyoD function and promoting myogenic differentiation. This work focuses on the characterization of two murine Cyclin T2 isoforms and the evaluation of the role of Cdk9/Cyclin T2 complexes during the skeletal muscle differentiation. This study demonstrated a predominant expression of isoform b in all stages of differentiation. Moreover, both isoforms of Cyclin T2 are able to activate the myogenic program but Cyclin T2b has a predominant role, in particular during the latest stages.
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PMID:Activation and function of murine Cyclin T2A and Cyclin T2B during skeletal muscle differentiation. 2306 74

Histone chaperones affect chromatin structure and gene expression through interaction with histones and RNA polymerase II (PolII). Here, we report that the histone chaperone Spt6 counteracts H3K27me3, an epigenetic mark deposited by the Polycomb Repressive Complex 2 (PRC2) and associated with transcriptional repression. By regulating proper engagement and function of the H3K27 demethylase KDM6A (UTX), Spt6 effectively promotes H3K27 demethylation, muscle gene expression, and cell differentiation. ChIP-Seq experiments reveal an extensive genome-wide overlap of Spt6, PolII, and KDM6A at transcribed regions that are devoid of H3K27me3. Mammalian cells and zebrafish embryos with reduced Spt6 display increased H3K27me3 and diminished expression of the master regulator MyoD, resulting in myogenic differentiation defects. As a confirmation for an antagonistic relationship between Spt6 and H3K27me3, inhibition of PRC2 permits MyoD re-expression in myogenic cells with reduced Spt6. Our data indicate that, through cooperation with PolII and KDM6A, Spt6 orchestrates removal of H3K27me3, thus controlling developmental gene expression and cell differentiation.
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PMID:The histone chaperone Spt6 coordinates histone H3K27 demethylation and myogenesis. 2350 87


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