title: TNF inhibits Notch-1 in skeletal muscle cells by Ezh2 and DNA methylation mediated repression: implications in duchenne muscular dystrophy.
abstract: BACKGROUND
  Classical NF-kappaB signaling functions as a negative regulator of skeletal myogenesis through potentially multiple mechanisms. The inhibitory actions of TNFalpha on skeletal muscle differentiation are mediated in part through sustained NF-kappaB activity. In dystrophic muscles, NF-kappaB activity is compartmentalized to myofibers to inhibit regeneration by limiting the number of myogenic progenitor cells. This regulation coincides with elevated levels of muscle derived TNFalpha that is also under IKKbeta and NF-kappaB control.
  
  
  RESULTS
  Based on these findings we speculated that in DMD, TNFalpha secreted from myotubes inhibits regeneration by directly acting on satellite cells. Analysis of several satellite cell regulators revealed that TNFalpha is capable of inhibiting Notch-1 in satellite cells and C2C12 myoblasts, which was also found to be dependent on NF-kappaB. Notch-1 inhibition occurred at the mRNA level suggesting a transcriptional repression mechanism. Unlike its classical mode of action, TNFalpha stimulated the recruitment of Ezh2 and Dnmt-3b to coordinate histone and DNA methylation, respectively. Dnmt-3b recruitment was dependent on Ezh2.
  
  
  CONCLUSIONS
  We propose that in dystrophic muscles, elevated levels of TNFalpha and NF-kappaB inhibit the regenerative potential of satellite cells via epigenetic silencing of the Notch-1 gene.
authors.affiliation: Human Cancer Genetics and Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Swarnali
authors.initials: S
authors.lastname: Acharyya
authors.forename: Sudarshana M
authors.initials: SM
authors.lastname: Sharma
authors.forename: Alfred S
authors.initials: AS
authors.lastname: Cheng
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Ladner
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: William
authors.initials: W
authors.lastname: Kline
authors.forename: Huating
authors.initials: H
authors.lastname: Wang
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
authors.forename: Tim H
authors.initials: TH
authors.lastname: Huang
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects*; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic / Q000235:genetics; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D051881:Receptor, Notch1; D014409:Tumor Necrosis Factor-alpha; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2
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