Activity-dependent gene regulation in skeletal muscle is mediated by a histone deacetylase (HDAC)-Dach2-myogenin signal transduction cascade.
Muscle activity contributes to muscle development and function largely by means of regulated gene expression. Many genes crucial to neuromuscular synapse formation, such as MuSK and nAChRs, are induced before muscle innervation or after muscle denervation, and this induction requires expression of the E-box binding, basic helix-loop-helix muscle-specific transcription factor, myogenin (Mgn). The mechanism by which muscle activity is coupled to gene expression is poorly defined. Here we report that inhibition of histone deacetylase (HDAC) activity attenuates the induction of activity-regulated genes in aneural myotubes and adult denervated muscle. The effect of HDAC inhibitors requires new protein synthesis, suggesting HDACs may regulate the expression of a Mgn transcriptional repressor. We identified Dach2 as a Mgn transcriptional repressor whose expression is dramatically reduced in an HDAC-dependent manner in developing aneural myotubes or adult denervated muscle. Dach2 overexpression in denervated muscle suppressed Mgn, nAChR, and MuSK gene induction, whereas Dach2 knockdown induced Mgn gene expression in innervated muscle and relieved Mgn promoter inhibition by HDAC inhibitors. Thus, a HDAC-Dach2-myogenin signaling pathway has been identified to decode nerve activity and control muscle gene expression in developing and adult skeletal muscle.
Tang
Huibin
H
Molecular and Behavioral Neuroscience Institute and Department of Biological Chemistry, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109, USA.
Goldman
Daniel
D
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D051379:Mice; D008959:Models, Neurological; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000254:growth & development / Q000294:innervation / Q000378:metabolism*; D018008:Myogenin / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors; D015533:Transcriptional Activation
D017931:DNA Primers; D004268:DNA-Binding Proteins; C485735:Dach2 protein, mouse; C503801:Myog protein, mouse; D018008:Myogenin; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D006655:Histone Deacetylases