Pbx homeodomain proteins direct Myod activity to promote fast-muscle differentiation

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Development (Impact Factor: 6.46). 10/2007; 134(18):3371-82. DOI: 10.1242/dev.003905
Source: PubMed

ABSTRACT The basic helix-loop-helix (bHLH) transcription factor Myod directly regulates gene expression throughout the program of skeletal muscle differentiation. It is not known how a Myod-driven myogenic program is modulated to achieve muscle fiber-type-specific gene expression. Pbx homeodomain proteins mark promoters of a subset of Myod target genes, including myogenin (Myog); thus, Pbx proteins might modulate the program of myogenesis driven by Myod. By inhibiting Pbx function in zebrafish embryos, we show that Pbx proteins are required in order for Myod to induce the expression of a subset of muscle genes in the somites. In the absence of Pbx function, expression of myog and of fast-muscle genes is inhibited, whereas slow-muscle gene expression appears normal. By knocking down Pbx or Myod function in combination with another bHLH myogenic factor, Myf5, we show that Pbx is required for Myod to regulate fast-muscle, but not slow-muscle, development. Furthermore, we show that Sonic hedgehog requires Myod in order to induce both fast- and slow-muscle markers but requires Pbx only to induce fast-muscle markers. Our results reveal that Pbx proteins modulate Myod activity to drive fast-muscle gene expression, thus showing that homeodomain proteins can direct bHLH proteins to establish a specific cell-type identity.

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    • "We next examined the binding of Pbx1 at the Myogenin promoter. Pbx1 is a homeodomain protein that has been implicated as a critical regulator of myogenin expression by targeting MyoD and chromatin remodeling enzymes to the myogenin promoter (Berkes et al., 2004; de la Serna et al., 2005; Maves et al., 2007). Pbx1 binding was clearly indicated at the five-somite stage by real-time PCR analysis (Fig. 1C). "
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    ABSTRACT: Background: Among the complexities of skeletal muscle differentiation is a temporal distinction in the onset of expression of different lineage-specific genes. The lineage-determining factor MyoD is bound to myogenic genes at the onset of differentiation whether gene activation is immediate or delayed. How temporal regulation of differentiation-specific genes is established remains unclear. Results: Using embryonic tissue, we addressed the molecular differences in the organization of the myogenin and muscle creatine kinase (MCK) gene promoters by examining regulatory factor binding as a function of both time and spatial organization during somitogenesis. At the myogenin promoter, binding of the homeodomain factor Pbx1 coincided with H3 hyperacetylation and was followed by binding of co-activators that modulate chromatin structure. MyoD and myogenin binding occurred subsequently, demonstrating that Pbx1 facilitates chromatin remodeling and modification before myogenic regulatory factor binding. At the same time, the MCK promoter was bound by HDAC2 and MyoD, and activating histone marks were largely absent. The association of HDAC2 and MyoD was confirmed by co-immunoprecipitation, proximity ligation assay (PLA), and sequential ChIP. Conclusions: MyoD differentially promotes activated and repressed chromatin structures at myogenic genes early after the onset of skeletal muscle differentiation in the developing mouse embryo.
    Developmental Dynamics 01/2015; 244(1). DOI:10.1002/dvdy.24217 · 2.38 Impact Factor
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    • "In zebrafish, Six1 and, most importantly, the Pbx homeodomain transcription factors have been implicated in the control of the onset of fast-muscle differentiation. In particular, it was recently demonstrated that Pbx acts by directing MyoD to a subset of fast-muscle genes, which counteracts the repressing action of Prdm1a [94, 109, 110]. "
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    ABSTRACT: Skeletal myogenesis has been and is currently under extensive study in both mammals and teleosts, with the latter providing a good model for skeletal myogenesis because of their flexible and conserved genome. Parallel investigations of muscle studies using both these models have strongly accelerated the advances in the field. However, when transferring the knowledge from one model to the other, it is important to take into account both their similarities and differences. The main difficulties in comparing mammals and teleosts arise from their different temporal development. Conserved aspects can be seen for muscle developmental origin and segmentation, and for the presence of multiple myogenic waves. Among the divergences, many fish have an indeterminate growth capacity throughout their entire life span, which is absent in mammals, thus implying different post-natal growth mechanisms. This review covers the current state of the art on myogenesis, with a focus on the most conserved and divergent aspects between mammals and teleosts.
    Cellular and Molecular Life Sciences CMLS 03/2014; 71(16). DOI:10.1007/s00018-014-1604-5 · 5.81 Impact Factor
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    • "Another important example of how Pbx homeodomain proteins act in a balance with other transcription factors to regulate cellular differentiation programs has been described in the muscle cell lineage (Berkes et al., 2004; Maves et al., 2007). Both Pbx and Meis exhibit genetic interactions in the regulation of myogenin expression and fast-muscle differentiation in zebrafish as well as Drosophila (Maves et al., 2007; Bryantsev et al., 2012). Pbx proteins have been found to physically bind to promoters of MyoD transcriptional targets, such as myogenin, in mammalian myoblast cell lines (Berkes et al., 2004). "
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    ABSTRACT: During embryonic development, cells become gradually restricted in their developmental potential and start elaborating lineage-specific transcriptional networks to ultimately acquire a unique differentiated state. Hox genes play a central role in specifying regional identities, thereby providing the cell with critical information on positional value along its differentiation path. The exquisite DNA-binding specificity of the Hox proteins is frequently dependent upon their interaction with members of the TALE family of homeodomain proteins. In addition to their function as Hox-cofactors, TALE homeoproteins control multiple crucial developmental processes through Hox-independent mechanisms. Here, we will review recent findings on the function of both Hox and TALE proteins in cell differentiation, referring mostly to vertebrate species. In addition, we will discuss the direct implications of this knowledge on cell plasticity and cell reprogramming. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc.
    Developmental Dynamics 01/2014; 243(1). DOI:10.1002/dvdy.24075 · 2.38 Impact Factor
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