MBNL3/CHCR prevents myogenic differentiation by inhibiting MyoD-dependent gene transcription

Authors

  • Kyung-Soon Lee,

    1. Department of Pharmacology, School of Medicine, University of Washington, 1959 NE Pacific Street, P. O. Box 357280, Seattle, WA 98195-7280, U.S.A.
      Tel: +1 206 616 5376
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  • Kimberly Smith,

    1. Department of Pharmacology, School of Medicine, University of Washington, 1959 NE Pacific Street, P. O. Box 357280, Seattle, WA 98195-7280, U.S.A.
      Tel: +1 206 616 5376
      Fax: +1206 685 3822
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  • Paul S. Amieux,

    1. Department of Pharmacology, School of Medicine, University of Washington, 1959 NE Pacific Street, P. O. Box 357280, Seattle, WA 98195-7280, U.S.A.
      Tel: +1 206 616 5376
      Fax: +1206 685 3822
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  • Edith H. Wang

    Corresponding author
    1. Department of Pharmacology, School of Medicine, University of Washington, 1959 NE Pacific Street, P. O. Box 357280, Seattle, WA 98195-7280, U.S.A.
      Tel: +1 206 616 5376
      Fax: +1206 685 3822
    Search for more papers by this author

✉ E-mail: ehwang@u.washington.edu

Abstract

Abstract Muscle differentiation is controlled by positive and negative signals. While much attention has been placed on proteins that promote muscle formation, the importance of negative regulators has been underemphasized. MBNL3/CHCR belongs to the muscleblind family of Cys3His zinc finger proteins implicated in myotonic dystrophy. MBNL3 is expressed in myoblasts, muscle precursor cells, and during the early stages of myogenesis, but is detected at very low levels in terminally differentiated myotubes. Constitutive expression of MBNL3 inhibits myotube formation and antagonizes myogenin and myosin heavy chain expression. To identify MBNL3 target genes, we compared the expression profile of C2C12 mouse myoblasts that constitutively express MBNL3 with control cells. From the 15,247 genes represented on the DNA microarray, classification by biological function indicated that genes involved in muscle development/contraction and cell adhesion were down-regulated by MBNL3 expression. mRNA and protein levels for the muscle transcription factor MyoD and E-box regulated transcription were reduced in C2C12-MBNL3 expressing cells. We hypothesize that MBNL3 serves to antagonize muscle differentiation by suppressing MyoD expression levels to prevent unwanted myogenic gene transcription. These findings are the first indication that a mammalian muscleblind-like (MBNL) protein plays a regulatory role in muscle differentiation under nonpathogenic conditions.

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