Review
MyoD and the transcriptional control of myogenesis

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Abstract

The basic helix-loop-helix myogenic regulatory factors MyoD, Myf5, myogenin and MRF4 have critical roles in skeletal muscle development. Together with the Mef2 proteins and E proteins, these transcription factors are responsible for coordinating muscle-specific gene expression in the developing embryo. This review highlights recent studies regarding the molecular mechanisms by which the muscle-specific myogenic bHLH proteins interact with other regulatory factors to coordinate gene expression in a controlled and ordered manner.

Introduction

The myogenic regulatory factors (MRFs) are critical for the determination and terminal differentiation of skeletal muscle. In the two decades since their discovery, in vivo studies have elucidated the specific roles of MyoD and its relatives Myf5, myogenin, and MRF4, and cell culture studies have uncovered the basic mechanisms by which they function in transcription. The MRFs, together with Mef2 family proteins and other general and muscle-specific factors, coordinate the activities of a host of co-activators and co-repressors, resulting in tight control of gene expression during myogenesis. The events occurring at muscle-specific promoters have been dissected in molecular detail, uncovering a multitude of functional and direct interactions between MRFs and signaling proteins, chromatin modifying factors, and other transcriptional regulators. Information regarding the genetic networks controlling myogenesis, the signaling networks that are deployed to initiate myogenesis in the developing somites, and the molecular mechanisms that mediate activation of muscle-specific genes has expanded considerably in the past several years. In this review, we will focus on the latter of these three subjects, with particular attention to the MyoD family of transcription factors.

Section snippets

The specification and differentiation of skeletal muscle by the MyoD family of bHLH proteins

Nearly 20 years ago, subtractive hybridization experiments were performed to identify and isolate myoblast-specific transcripts that were capable of orchestrating myogenic conversion of 10T1/2 fibroblasts [1], [2]. This work led to the identification of a single cDNA, named MyoD, which was capable of converting a variety of cell types (e.g., fibroblasts, chondrocytes, neurons, amniocytes) to myoblasts [3], [4], [5]. MyoD belongs to a much larger class of DNA-binding proteins containing a basic

Role of E proteins

MRFs are class II (tissue-specific) bHLH transcription factors and are capable of either homo-dimerization with themselves, or heterodimerization with class I bHLH factors. Class I factors, which include the E proteins HEB/HTF4, E2-2/ITF-2, and E12/E47, are ubiquitously expressed in various tissues and at different times during development. The basic region is required for DNA-binding, whereas the HLH domain mediates dimerization with other bHLH proteins. All bHLH dimers bind to a consensus

Inhibitors of myogenic transcription

MyoD is expressed in myoblasts well before activation of its target genes, both in vivo and in tissue culture systems. There are several well-described mechanisms by which premature activity of MyoD is prevented: post-translational modification, association with co-repressor proteins, and association with proteins which titrate MyoD away from the DNA. Post-translational modifications and co-repressors of MyoD will be addressed under “The Role of Coactivators and Corepressors in Controlling

Other myogenic activators

The MRFs are assisted by the myocyte enhancer factor 2 (Mef2) family of transcription factors in order to mediate expression of muscle-specific genes (reviewed in [41]). Mef2 proteins belong to the MADS (MCM1, agamous, deficiens, serum response factor) box-containing transcription factor family. The Mef2 family consists of four members, Mef2A-D, each of which is encoded on a separate gene. While expression of MRFs is restricted to muscle, Mef2 genes are expressed widely during development. Mef2

Functional domains of MyoD

The MRFs are distinct from all other bHLH proteins in that each contains a conserved muscle recognition motif within the basic domain comprised of three amino acids; this myogenic “code”, comprised of the amino acids ATK, confers the ability to activate muscle-specific genes [84], [85]. These amino acid residues are required for cooperativity between MyoD and Mef2 on both endogenous muscle genes [43] and transfected reporters [86], providing strong evidence that at least part of the function of

Myogenic targets

MyoD activation leads to robust expression of several well-characterized target genes such as myogenin, M-cadherin, myosin heavy and light chains, and muscle creatine kinase. In addition to these muscle-specific genes, it has also been well-established that MyoD up-regulates expression of the cyclin-dependent kinase inhibitor p21Waf/Cip1, causing an irreversible exit of the differentiating cells from the cell cycle [90], [91]. We and others have characterized expression of genes during

The role of co-activators and co-repressors in controlling myogenic transcription

Three classes of co-activators are known to cooperate with transcription factors to mediate specific and patterned gene expression: histone modifying proteins such as histone acetylases and methylases, SWI/SNF family chromatin remodeling factors, and proteins in the TRAP/Mediator family. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) both interact with MyoD and have opposing activities that might be critical to switch MyoD from a repressor to an activator at some loci, which

Control of myogenesis via signaling pathways

The p38 kinase has a particularly robust role in expression of muscle-specific genes, and the specific mechanisms by which p38 impinges upon the muscle gene regulatory pathway have been well-described in recent papers. p38 kinase activity increases over the course of skeletal muscle differentiation and its activity is required for terminal differentiation [127]. p38 functions, in part, by phosphorylating the transactivation domain of Mef2 [128], [129], [130], [131] and inhibition of p38 stifles

Putting together pieces of the puzzle

In the past several years, we have learned a great deal regarding the factors associating with muscle-specific promoters and enhancers, and have described gene expression during myogenesis on a genome-wide level [92], [94]. The mechanisms by which chromatin structure regulate gene expression have been well-described in many other systems. The remaining challenge will be to put the pieces together to synthesize a coherent picture of myogenic transcriptional regulation. It is well-established

References (140)

  • L.A. Neuhold et al.

    HLH forced dimers: tethering MyoD to E47 generates a dominant positive myogenic factor insulated from negative regulation by Id

    Cell

    (1993)
  • J.D. Molkentin et al.

    Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins

    Cell

    (1995)
  • W.W. Wasserman et al.

    Identification of muscle regulatory regions which confer muscle-specific gene expression

    J Mol Biol

    (1998)
  • R. Chen et al.

    Dachshund and eyes absent proteins form a complex and function synergistically to induce ectopic eye development in Drosophila

    Cell

    (1997)
  • F. Pignoni et al.

    The eye-specification proteins So and Eya form a complex and function synergistically to induce ectopic eye development in Drosophila

    Cell

    (1997)
  • C.A. Berkes et al.

    Pbx marks genes for activation by MyoD indicating a role for a homeodomain protein in establishing myogenic potential

    Mol Cell

    (2004)
  • A.J. Waskiewicz et al.

    Eliminating zebrafish Pbx proteins reveals a hindbrain ground state

    Dev Cell

    (2002)
  • M.P. Kamps et al.

    A new homeobox gene contributes the DNA-binding domain of the t(1;19) translocation protein in pre-B ALL

    Cell

    (1990)
  • J. Nourse et al.

    Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor

    Cell

    (1990)
  • R.S. Mann et al.

    Hox proteins meet more partners

    Curr Opin Genet Dev

    (1998)
  • Y. Liu et al.

    DNA-binding and transcriptional activation by a Pdx1-Pbx1b-Meis2b trimer and cooperation with a pancreas-specific basic helix-loop-helix complex

    J Biol Chem

    (2001)
  • J.W. Rhee et al.

    Pbx3 deficiency results in central hypoventilation

    Am J Pathol

    (2004)
  • K. Wagner et al.

    Pbx4, a new Pbx family member on mouse chromosome 8, is expressed during spermatogenesis

    Mech Dev

    (2001)
  • S. Arber et al.

    Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation

    Cell

    (1994)
  • R.L. Davis et al.

    The MyoD DNA-binding domain contains a recognition code for muscle-specific gene activation

    Cell

    (1990)
  • D.A. Bergstrom et al.

    Promoter-specific regulation of MyoD binding and signal transduction cooperate to pattern gene expression

    Mol Cell

    (2002)
  • I. Delgado et al.

    Dynamic gene expression during the onset of myoblast differentiation in vitro

    Genomics

    (2003)
  • P. Zhao et al.

    In vivo filtering of in vitro expression data reveals MyoD targets

    C R Biol

    (2003)
  • P.L. Puri et al.

    Differential roles of p300 and PCAF acetyltransferases in muscle differentiation

    Mol Cell

    (1997)
  • S.F. Konieczny et al.

    Myogenic determination and differentiation in 10T1/2 cell lineages: evidence for a simple genetic regulatory system

    Mol Cell Biol

    (1988)
  • J. Choi et al.

    MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigment epithelial cells into striated, mononucleated myoblasts and multinucleated myotubes

    Proc Natl Acad Sci USA

    (1990)
  • H. Weintraub et al.

    Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD

    Proc Natl Acad Sci USA

    (1989)
  • H. Weintraub et al.

    The MyoD gene family: nodal point during specification of the muscle cell lineage

    Science

    (1991)
  • T.K. Blackwell et al.

    Differences and similarities in DNA-binding preferences of MyoD and E2A protein complexes revealed by binding site selection

    Science

    (1990)
  • T. Braun et al.

    A novel human muscle factor related to but distinct from MyoD1 induces myogenic conversion in 10T1/2 fibroblasts

    EMBO J

    (1989)
  • D.G. Edmondson et al.

    A gene with homology to the myc similarity region of MyoD1 is expressed during myogenesis and is sufficient to activate the muscle differentiation program

    Genes Dev

    (1989)
  • J.H. Miner et al.

    Herculin, a fourth member of the MyoD family of myogenic regulatory genes

    Proc Natl Acad Sci USA

    (1990)
  • B. Kablar et al.

    MyoD and Myf5 define the specification of musculature of distinct embryonic origin

    Biochem Cell Biol

    (1998)
  • P. Hasty et al.

    Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene

    Nature

    (1993)
  • Y.K. Nabeshima et al.

    Myogenin gene disruption results in perinatal lethality because of severe muscle defect

    Nature

    (1993)
  • Y. Wang et al.

    Myogenin can substitute for Myf5 in promoting myogenesis but less efficiently

    Development

    (1997)
  • D.A. Bergstrom et al.

    Molecular distinction between specification and differentiation in the myogenic basic helix-loop-helix transcription factor family

    Mol Cell Biol

    (2001)
  • Z. Zhu et al.

    MRF4 can substitute for myogenin during early stages of myogenesis

    Dev Dyn

    (1997)
  • V.M. Sumariwalla et al.

    Similar myogenic functions for myogenin and MRF4 but not MyoD in differentiated murine embryonic stem cells

    Genesis

    (2001)
  • L. Kassar-Duchossoy et al.

    Mrf4 determines skeletal muscle identitiy in Myf5:MyoD double-mutant mice

    Nature

    (2004)
  • C. Chanoine et al.

    Myogenic regulatory factors: redundant or specific functions? Lessons from Xenopus

    Dev Dyn

    (2004)
  • K.E. Yutzey et al.

    Differential trans-activation associated with the muscle regulatory factors MyoD1, myogenin, and MRF4

    Mol Cell Biol

    (1990)
  • J.B. Scales et al.

    Two distinct Xenopus genes with homology to MyoD1 are expressed before somite formation in early embryogenesis

    Mol Cell Biol

    (1990)
  • A.M. Michelson et al.

    Expression of a MyoD family member prefigures muscle pattern in Drosophila embryos

    Genes Dev

    (1990)
  • J.M. Venuti et al.

    A myogenic factor from sea urchin embryos capable of programming muscle differentiation in mammalian cells

    Proc Natl Acad Sci USA

    (1991)
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