A MyoD-generated feed-forward circuit temporally patterns gene expression during skeletal muscle differentiation

Penn, Bennett H.; Bergstrom, Donald A.; Dilworth, F. Jeffrey; Bengal, Eyal; Tapscott, Stephen J.

doi:10.1101/gad.1234304

Cited by 165 publications

(174 citation statements)

References 29 publications

(40 reference statements)

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“…Given MEF2A transcriptional autoregulation, it is not surprising that we observed sensitivity of MEF2A transcription and steadystate mRNA abundance to p38 signaling. Because p38 activity both stimulates and is required for myogenesis (7,66,(71)(72)(73)(74), MAPK-mediated stimulation of MEF2A autoregulation is likely to be involved. MEF2 factors can tether to DNA-bound bHLH factors at E boxes (53) and to Sp1 at GC boxes (49).…”

Section: Discussionmentioning

confidence: 99%

Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

Ramachandran

et al. 2008

Journal of Biological Chemistry

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MEF2 (myocyte enhancer factor 2) proteins are a small family of transcription factors that play pivotal roles in striated muscle differentiation, development, and metabolism, in neuron survival and synaptic formation, and in lymphocyte selection and activation. Products of the four mammalian MEF2 genes, MEF2A, MEF2B, MEF2C, and MEF2D, are expressed with overlapping but distinct temporospatial patterns. Toward analysis of MEF2A functions and the determinants of its regulated expression, we have mapped and begun studies of the transcriptional control regions of this gene. Heterogeneous 5 -untranslated regions of MEF2A mRNAs result from use of alternative promoters and splicing patterns. The two closely approximated TATA-less promoters are ϳ65 kb upstream of the exon containing the sole initiation codon. Ribonuclease protection and primer extension assays show that each promoter is active in various adult tissues. A canonical MEF2 site overlies the major promoter 1 transcription start site. This element specifically binds MEF2 factors, including endogenous nuclear MEF2A according to chromatin immunoprecipitation studies, and is critical to MEF2A transcription in myocytes. The site exerts reciprocal control of the alternative promoters, silencing promoter 1 and activating promoter 2 under some conditions. Erk5 and p38 MAPK signaling stimulate MEF2A expression by activating both promoters from the MEF2 element. MEF2A transcription is therefore subject to positive or negative regulation by its protein products, depending on signaling activities that influence MEF2 factor trans-activity. The sole MEF2 gene of the cephalochordate amphioxus has a similar regulatory region structure, suggesting that this mode of autoregulatory control is conserved among higher metazoan MEF2 genes.

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Section: Discussionmentioning

confidence: 99%

Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

Ramachandran

et al. 2008

Journal of Biological Chemistry

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“…Nevertheless, other mechanisms may also contribute to temporal programs of muscle gene expression. For example, in a mammalian muscle cell culture model there is a MyoD-activated feed-forward circuit (41). Moreover, even though Pha4 has a dominant role in pharynx development, other factors modulate its action (42), and it is very likely that there are also additional inputs for Mef2 and muscle.…”

Section: Discussionmentioning

confidence: 99%

mef2 activity levels differentially affect gene expression during Drosophila muscle development

Elgar

Han

Taylor

2008

Proc. Natl. Acad. Sci. U.S.A.

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Cell differentiation is controlled by key transcription factors, and a major question is how they orchestrate cell-type-specific genetic programs. Muscle differentiation is a well studied paradigm in which the conserved Mef2 transcription factor plays a pivotal role. Recent genomic studies have identified a large number of mef2-regulated target genes with distinct temporal expression profiles during Drosophila myogenesis. However, the question remains as to how a single transcription factor can control such diverse patterns of gene expression. In this study we used a strategy combining genomics and developmental genetics to address this issue in vivo during Drosophila muscle development. We found that groups of mef2-regulated genes respond differently to changes in mef2 activity levels: some require higher levels for their expression than others. Furthermore, this differential requirement correlates with when the gene is first expressed during the muscle differentiation program. Genes that require higher levels are activated later. These results implicate mef2 in the temporal regulation of muscle gene expression, and, consistent with this, we show that changes in mef2 activity levels can alter the start of gene expression in a predictable manner. Together these results indicate that Mef2 is not an all-or-none regulator; rather, its action is more subtle, and levels of its activity are important in the differential expression of muscle genes. This suggests a route by which mef2 can orchestrate the muscle differentiation program and contribute to the stringent regulation of gene expression during myogenesis. muscle differentiation program ͉ transcription factor levels F or several decades it has been appreciated that the controlled regulation of gene expression, including the coordinated activation of batteries of genes, lies behind cell differentiation programs (1-3). It is now clear that a principle tier of control of cell differentiation is through key transcription factors, and an important general question is how these factors coordinate the genetic program of such complex processes. A classic paradigm is muscle, in which the conserved Mef2 transcription factor is a major regulator of gene expression and differentiation (4). Mef2 was first identified in mammalian cell culture (5-7), but because mammals possess four closely related mef2 genes functional analyses during development are complicated. In contrast, Drosophila has a single mef2 gene and was the first organism to be used to show that mef2 is required for muscle development in vivo (8)(9)(10). This highlighted that the analysis of how mef2 functions is central to understanding how muscle is made. Important characteristics of the underlying genetic program include the temporal coordination of muscle gene expression (11-13) and the regulation of levels and relative stoichiometries of gene expression during myogenesis (14-19). Although these basic features have been known for many years, much remains to be understood about them. However, the identificati...

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“…It is becoming increasingly evident that MyoD (and perhaps other myogenic regulatory factors), rather than indiscriminately activating transcription of all of its possible targets at once, differentially regulates muscle gene expression. Discrete signaling cascades and specific domains of MyoD impart transcription of distinct subsets of genes (14,22,41). Moreover, MyoD-associated cofactors influence its ability to activate some targets but not others (16,42).…”

Section: Discussionmentioning

confidence: 99%

MyoD Acetylation Influences Temporal Patterns of Skeletal Muscle Gene Expression

Padova

Caretti

Zhao

et al. 2007

Journal of Biological Chemistry

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MyoD is sufficient to initiate the skeletal muscle gene expression program. Transcription of certain MyoD target genes occurs in the early phases, whereas that of others is induced only at later stages, although MyoD is present throughout the differentiation process. MyoD acetylation regulates transcriptional competency, yet whether this post-translational modification is equally relevant for activation of all the MyoD targets is unknown. Moreover, the molecular mechanisms through which acetylation ensures that MyoD achieves its optimal activity remain unexplored. To address these two outstanding issues, we have coupled genome-wide expression profiling and chromatin immunoprecipitation in a model system in which MyoD or its nonacetylatable version was inducibly activated in mouse embryonic fibroblasts derived from MyoD ؊/؊ /Myf5 ؊/؊ mice. Our results reveal that MyoD acetylation influences transcription of selected genes expressed at defined stages of the muscle program by regulating chromatin access of MyoD, histone acetylation, and RNA polymerase II recruitment.MyoD, Myf5, myogenin, Mrf4, and the Mef2 family of MADS box transcription factors are the prominent regulators of skeletal myogenesis (1-3). MyoD and Mef2 recruit enzymes that introduce post-translational histone modifications at the chromatin of specific genomic loci to enable site-specific and temporally regulated muscle gene expression (4). MyoD engages at least two acetyltransferases, p300 and PCAF (5), which promote acetylation of both histones and of MyoD itself. p300 and PCAF acetylate evolutionarily conserved MyoD lysines, which, when mutated to arginines, prevent full and proper transcriptional activity (6 -9). In vitro transcription experiments have indicated that although p300 acetylation is directed at histones H3 and H4, it is PCAF that acetylates MyoD (10). The functional relevance of MyoD acetylation in the animal has been confirmed in a recent study. Knock-in embryos homozygous for a mutant MyoD allele in which lysines 99 and 102 were replaced by arginines had delayed muscle regeneration and increased number of myoblasts with reduced differentiation potential (11). Although these studies indicate an overall important role of MyoD acetylation in both cultured cells and in the animal, a detailed investigation of whether MyoD acetylation impacts the temporal activation of the individual components of the muscle program is lacking. Moreover, the molecular mechanisms leading to defective transcription of nonacetylatable MyoD have not been clarified yet.To evaluate the contribution of MyoD acetylation at distinct, temporal-specific, stages of muscle gene activation, we have performed reiterated genome-wide expression profiling and chromatin immunoprecipitation of mouse embryonic fibroblasts (MEFs) 4 derived from MyoD Ϫ/Ϫ /Myf5 Ϫ/Ϫ animals in which MyoD activity (wild type or nonacetylatable forms) was conditionally induced. Our results indicate that acetylation is relevant to regulate a discrete set of genes at distinct stages of muscle gene e...

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A MyoD-generated feed-forward circuit temporally patterns gene expression during skeletal muscle differentiation

Cited by 165 publications

References 29 publications

Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

mef2 activity levels differentially affect gene expression during Drosophila muscle development

MyoD Acetylation Influences Temporal Patterns of Skeletal Muscle Gene Expression

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