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Published August 1, 2008 | Supplemental Material + Published
Journal Article Open

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.

Additional Information

© 2008 Cold Spring Harbor Laboratory Press. The Authors acknowledge that six months after the full-issue publication date, the Article will be distributed under a Creative Commons CC-BY-NC License (Attribution-NonCommercial 4.0 International License, http://creativecommons.org/licenses/by-nc/4.0/). Received January 3, 2008; revised version accepted June 4, 2008. We thank Shirley Pease (Laboratory Animal Resource, Caltech) for transgenic production, Marcello Coletta for technical help in denervation experiments, Leslie Dunipace for technical assistance, Dr. Carlos Lois for parental lentiviral vectors, Dr. Cathy Yuh for help in Affinity Chromatography procedures, Dr. Dario Coletti for help in mice leg electroporation, Hiroke Shizuya for mouse BAC library, Diane Trout for MUSSAGL and genome comparison figures; and Dr. Johannes Graumann for MudPIT analysis performed in the Caltech Beckman Institute PEL center. We are grateful to Drs. C. Berkes and Stephen Tapscott for valuable discussion and exchange of reagents results prior to publication. We also acknowledge Dr. Pier Lorenzo Puri for helpful discussion. This work was supported by NIH, DOE, and NASA grants to B.J.W. and Fondation Leducq, BMW, Duchenne Parent Project, FIRB, and EcMyoAmp grants to G.C.

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