title: TGF-beta regulates miR-206 and miR-29 to control myogenic differentiation through regulation of HDAC4.
abstract: MicroRNAs (miRs) are emerging as prominent players in the regulation of many biological processes, including myogenic commitment and skeletal muscle formation. Members of the TGF-β family can influence the proliferation and myogenic differentiation of cells, although it is presently not clear what role miRNAs play in the TGF-β-mediated control of myogenic differentiation. Here, we demonstrate in the myogenic C2C12 cell line, and in primary muscle cells, that miR-206 and miR-29-two miRs that act on transcriptional events implicated in muscle differentiation are down-regulated by TGF-β. We further demonstrate that TGF-β treatment of myogenic cells is associated with increased expression of histone deacetylase 4 (HDAC4), a key inhibitor of muscle differentiation that has been identified as a target for regulation by miR-206 and miR-29. We confirmed that increased expression of miR-206 and miR-29 resulted in the translational repression of HDAC4 in the presence or absence of TGF-β via interaction with the HDAC4 3'-untranslated region. Importantly, we found that miR-206 and miR-29 can attenuate the inhibitory actions of TGF-β on myogenic differentiation. Furthermore, we present evidence that the mechanism by which miR-206 and miR-29 can inhibit the TGF-β-mediated up-regulation of HDAC4 is via the inhibition of Smad3 expression, a transducer of TGF-β signaling. These findings identify a novel mechanism of interaction between TGF-β and miR-206 and -29 in the regulation of myogenic differentiation through HDAC4.
authors.affiliation: Division of Metabolism and Obesity, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 8008, Australia.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Claudia
authors.initials: C
authors.lastname: Beyer
authors.forename: Phillip
authors.initials: P
authors.lastname: Koh
authors.forename: Lloyd
authors.initials: L
authors.lastname: White
authors.forename: Phillip
authors.initials: P
authors.lastname: Kantharidis
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D024510:Muscle Development; D009132:Muscles / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; D016212:Transforming Growth Factor beta; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases