A highly conserved molecular switch binds MSY-3 to regulate myogenin repression in postnatal muscle.
Myogenin is the dominant transcriptional regulator of embryonic and fetal muscle differentiation and during maturation is profoundly down-regulated. We show that a highly conserved 17-bp DNA cis-acting sequence element located upstream of the myogenin promoter (myogHCE) is essential for postnatal repression of myogenin in transgenic animals. We present multiple lines of evidence supporting the idea that repression is mediated by the Y-box protein MSY-3. Electroporation in vivo shows that myogHCE and MSY-3 are required for postnatal repression. We further show that, in the C2C12 cell culture system, ectopic MSY-3 can repress differentiation, while reduced MSY-3 promotes premature differentiation. MSY-3 binds myogHCE simultaneously with the homeodomain protein Pbx in postnatal innervated muscle. We therefore propose a model in which the myogHCE motif operates as a switch by specifying opposing functions; one that was shown previously is regulated by MyoD and Pbx and it specifies a chromatin opening, gene-activating function at the time myoblasts begin to differentiate; the other includes MYS-3 and Pbx, and it specifies a repression function that operates during and after postnatal muscle maturation in vivo and in myoblasts before they begin to differentiate.
Berghella
Libera
L
Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park, Rome 00128, Italy. libera.berghella@spr-r.it
De Angelis
Luciana
L
De Buysscher
Tristan
T
Mortazavi
Ali
A
Biressi
Stefano
S
Forcales
Sonia V
SV
Sirabella
Dario
D
Cossu
Giulio
G
Wold
Barbara J
BJ
D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018274:Electroporation; D005786:Gene Expression Regulation / Q000502:physiology*; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D018482:Muscle, Skeletal / Q000254:growth & development*; D017570:MyoD Protein / Q000235:genetics / Q000502:physiology; D032446:Myoblasts / Q000502:physiology; D018008:Myogenin / Q000235:genetics* / Q000502:physiology; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D017570:MyoD Protein; D018008:Myogenin; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C415142:Y box protein 3, mouse