title: The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy.
abstract: Elucidating the epigenetic mechanisms underlying muscle mass determination and skeletal muscle wasting holds the potential of identifying molecular pathways that constitute possible drug targets. Here, we report that the methyltransferase SMYD3 modulates myostatin and c-Met transcription in primary skeletal muscle cells and C2C12 myogenic cells. SMYD3 targets the myostatin and c-Met genes and participates in the recruitment of the bromodomain protein BRD4 to their regulatory regions through protein-protein interaction. By recruiting BRD4, SMYD3 favors chromatin engagement of the pause-release factor p-TEFb (positive transcription elongation factor) and elongation of Ser2-phosphorylated RNA polymerase II (PolIISer2P). Reducing SMYD3 decreases myostatin and c-Met transcription, thus protecting from glucocorticoid-induced myotube atrophy. Supporting functional relevance of the SMYD3/BRD4 interaction, BRD4 pharmacological blockade by the small molecule JQ1 prevents dexamethasone-induced myostatin and atrogene up-regulation and spares myotube atrophy. Importantly, in a mouse model of dexamethasone-induced skeletal muscle atrophy, SMYD3 depletion prevents muscle loss and fiber size decrease. These findings reveal a mechanistic link between SMYD3/BRD4-dependent transcriptional regulation, muscle mass determination, and skeletal muscle atrophy and further encourage testing of small molecules targeting specific epigenetic regulators in animal models of muscle wasting.
authors.affiliation: Department of Biosciences, University of Milan, 20133 Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Proserpio
authors.forename: Raffaella
authors.initials: R
authors.lastname: Fittipaldi
authors.forename: James G
authors.initials: JG
authors.lastname: Ryall
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sartorelli
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Caretti
mesh_terms: D000818:Animals; D002460:Cell Line; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000139:chemically induced / Q000235:genetics*; D055435:Myostatin / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012319:RNA Polymerase II / Q000737:chemistry / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
chemical_list: D042863:Cyclin-Dependent Kinase 9; D003907:Dexamethasone; D011495:Histone-Lysine N-Methyltransferase; D009124:Muscle Proteins; D055435:Myostatin; D009687:Nuclear Proteins; D010768:Phosphoserine; D042925:Positive Transcriptional Elongation Factor B; D019859:Proto-Oncogene Proteins c-met; D012319:RNA Polymerase II; D044843:SKP Cullin F-Box Protein Ligases; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C582787:Smyd3 protein, mouse; C486691:Fbxo32 protein, mouse; C467972:Cdk9 protein, mouse
keywords: BRD4; SMYD3; muscle atrophy; myostatin