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. 2010 Jan-Mar;6(1):48–53. doi: 10.4161/org.6.1.11293

Epigenetic regulation of skeletal myogenesis

Valentina Saccone 1, Pier Lorenzo Puri 1,2,
PMCID: PMC2861743  PMID: 20592865

Abstract

During embryogenesis a timely and coordinated expression of different subsets of genes drives the formation of skeletal muscles in response to developmental cues. In this review, we will summarize the most recent advances on the “epigenetic network” that promotes the transcription of selective groups of genes in muscle progenitors, through the concerted action of chromatin-associated complexes that modify histone tails and microRNAs (miRNAs). These epigenetic players cooperate to establish focal domains of euchromatin, which facilitates gene transcription, and large portions of heterochromatin, which precludes inappropriate gene expression. We also discuss the analogies and differences in the transcriptional and the epigenetic networks driving developmental and adult myogenesis. The elucidation of the epigenetic basis controlling skeletal myogenesis during development and adult life will facilitate experimental strategies toward generating muscle stem cells, either by reprogramming embryonic stem cells or by inducing pluripotency in adult skeletal muscles. During embryogenesis a timely and coordinated expression of different subsets of genes drives the formation of skeletal muscles in response to developmental cues. In this review, we will summarize the most recent advances on the “epigenetic network” that promotes the transcription of selective groups of genes in muscle progenitors, through the concerted action of chromatin-associated complexes that modify histone tails and microRNAs (miRNAs). These epigenetic players cooperate to establish focal domains of euchromatin, which facilitates gene transcription, and large portions of heterochromatin, which precludes inappropriate gene expression. We also discuss the analogies and differences in the transcriptional and the epigenetic networks driving developmental and adult myogenesis. The elucidation of the epigenetic basis controlling skeletal myogenesis during development and adult life will facilitate experimental strategies toward generating muscle stem cells, either by reprogramming embryonic stem cells or by inducing pluripotency in adult skeletal muscles.

Key words: epigenetics, gene expression, skeletal myogenesis, chromatin, miRNA

Introduction

The vertebrate skeletal musculature is composed of functionally discrete structures (myofibers) that are generated by a number of distinct morphogenetic events during embryogenesis and are continuously remodelled during adult life by a physiological nuclear turnover and by the repair of injured fibers.

During embryogenesis, somite formation is a multi-factorial process, regulated by distinct networks of genes that respond to extrinsic cues released by the developmental environment, which mainly consists of cells from adjacent structures. These extremely dynamic networks coordinate the morphological and functional modifications in the somites and culminate in the formation of the contractile units that compose the adult skeletal muscles. Skeletal muscles stem from the middle germinal layer, which contains a specific cell type (the “mesoblast”) that migrates between other cell types, such as hypoblasts and epiblasts, to form a middle germinal layer, called mesoderm. The mesoderm on both sides of the neural tube—paraxial mesoderm—gives rise to the somites, the paired structures that contain the precursors of skeletal muscles. Somites lie lateral to the neural tube and nothocord, and then differentiate into the skeletal musculature (myotome), the skin (dermatome) and the skeletal axis (sclerotome)1 (Fig. 1).

Figure 1.

Figure 1

A schematic representation of developmental myogenesis shows the anatomy of the embryo structures that give rise to muscle progenitors (somites) and instruct them by paracrine signals (e.g., neural tube and nothocord).

In post-natal life, adult skeletal muscles retain a heterogeneous population of muscle progenitors (satellite cells), which appear to be under the control of a transcriptional network reminiscent of that operating during somitogenesis;2,3 however, the obvious differences in the anatomical position, in the interactions with neighboring cells, and other morphological and functional distinctions suggest the existence of specific regulatory networks in embryonic vs adult skeletal muscle progenitors.4

During somite maturation, a population of progenitor cells from the central portion of the dermomyotome, that are destined to become myoblasts, express the paired domain and homeobox-containing transcription factors Pax3 and Pax7.5 Subsequently, these cells receive instructive signals from the surrounding tissues, to induce (Wnts, Sonic Hedgehog, Noggin) or inhibit (BMP4) the expression of the muscle regulatory factors (MRF) Myf5 and MyoD, which, together with MRF4, commit progenitor cells toward the myogenic lineage and provide them with the competence to differentiate into the skeletal muscles.6,7 A distinct population of muscle progenitors8 that does not differentiate into skeletal muscles during embryogenesis and remains associated to the myofibers forms a pool of “reserve” muscle stem cells, called satellite cells, whose primary function consists of mediating postnatal muscle growth and repair.911 Satellite cells are localized under the basal lamina, and are typically quiescent in adult resting muscle; however, they retain the ability to become activated in response to muscle damage, to repair injured muscles.12

In the following paragraphs, we will summarize the epigenetic mechanism that controls gene expression in muscle progenitors during development and adult life.

The Transcriptional Networks Orchestrating Skeletal Myogenesis during Embryogenesis and Regeneration

Tissue development and regeneration share common features. For istance, the components of the transcriptional network that regulates lineage specification, maintenance and cellular differentiation in somitic muscle progenitors and satellite cells appear to be the same or to belong to the same families of transcription and co-regulatory factors. In particular, the temporal and functional relationship between Pax3/Pax7 and MyoD/Myf5 appears to form a common axis that regulates the transcription of muscle specific genes in all muscle progenitors and promotes their differentiation into contractile myofibers.4,5 Pax3 and Pax7 are typically expressed in muscle progenitors prior to the expression of the myogenic basic helix-loop-helix (bHLH) proteins MyoD and Myf5, and solid evidence established a functional hierarchy between these factors, with Pax3 and Pax7 being essential activators of MyoD and Myf5 transcription in muscle cells.6 Since Pax3 and Pax7 can be found in other cell types, whereas myogenic bHLH proteins are specifically expressed in muscle cells, it is assumed that the Pax-mediated activation of myogenic bHLH factors is the key “molecular event” underlying the commitment toward the skeletal muscle lineage.

Skeletal muscle cells derive from two distinct lineages in the somite, with MyoD and Myf5 driving two spatially distinct differentiation programs.13,14 Early (epaxial) myogenesis is entirely dependent upon Myf5 and/or Mrf4,15 that are induced by signals from the neural tube/notochord complex. Subsequently, signals from the dorsal ectoderm activate MyoD in cells of the dorsolateral domain of somites, leading to hypaxial myogenesis, which generates the large majority of skeletal muscles (body wall, limbs, tongue and diaphragm).

MyoD and Myf5 and the other myogenic bHLH proteins, MRF4 and myogenin, bind to the same DNA consensus sites (E-boxes) on the regulatory regions of muscle-specific genes, thereby activating the muscle differentiation program, in cooperation with the MEF2 proteins, which bind to DNA sequences adjacent to the E-boxes.16,17 When ectopically introduced into somatic cells, MyoD and, less efficiently, the other myogenic bHLH factors reprogram the host genome toward the skeletal muscle lineage, a process referred to as “myogenic conversion”.18,19 This potential depends on MyoD ability to penetrate and remodel the chromatin at previously silent muscle loci.20 Muscle bHLH proteins start and carry on the differentiation program by dimerizing with the ubiquitously expressed E2A gene products (E12, E47 and HEB) and by functional interactions with MEF2 proteins and other downstream genes that amplify the process of skeletal myogenesis by recruiting a variety of chromatin-modifying enzymes.21

As development proceeds, the secondary wave of myogenesis takes place to generate adult skeletal muscles and the associated satellite cells, which are located under the basal lamina of the myofibres. Pax7 expression is known to be essential for the specification and possibly the initial expansion of the satellite cell population.22,23 However, recent studies seem to limit the importance of Pax7 in adult myogenesis. Lepper et al. showed that Pax7 is required for early juvenile muscle growth, when progenitor cells make the transition into quiescence, but it is not necessary for muscle regeneration at later stages of adult life.24 Following mechanical injury, satellite cells are activated, leave their niche and move outside of the basal lamina, proliferate and co-express Pax7 and MyoD.25 The descendants of activated satellite cells, the skeletal myoblasts, undergo multiple rounds of division and the segregation of different transcription factors dictates the fate of two distinct populations. In particular, Pax7 expression appears to co-segregate with the fraction of satellite cells that do not enter the differentiation program, while the expression of MyoD and Myf5 marks the population committed to the differentiation program.25,26 These populations likely reflect the asymmetric division of the satellite cells, thereby revealing their stemness.27,28

Despite of the apparent analogies and redundancies in the molecular machinery that governs developmental and adult skeletal myogenesis, the instructive signaling to the muscle progenitors during somitogenesis and regeneration is different. Thus, components of a common transcription machinery that control skeletal myogenesis can be differently coordinated by context-specific signaling pathways.

The Epigenetic Networks that Control Skeletal Myogenesis

The transcriptional network that regulates the myogenic program is underpinned by specific epigenetic modifications that regulate muscle progenitors progression in response to environmental cues. These cues are converted into the nuclear information necessary to reprogram the genome of muscle cells, by a number of chromatin modifications that establish key epigenetic marks at particular loci. The combination of different post-translational modification of histone tails (acetylation, methylation, phosphorylation, ubiquitination)29 impart to the chromatin the configuration that facilitates or represses the transcription of target genes during the nuclear reprogramming of muscle cells undergoing differentiation.21 A number of chromatin-associated complexes endowed with an enzymatic activity toward histones have been discovered in the last decade, and have changed our interpretation of the molecular regulation of muscle genes transcription.

Chromatin modifications at muscle specific loci.

The epigenetic profile of every cell type is determinated by the balance between co-activators and co-repressors and the post-transcriptional modifications of histone tails.29

In undifferentiated myoblasts, the unscheduled activation of the differentiation program is precluded by recruitment of histone deacetylases (HDACs) on the chromatin of muscle genes. Class I HDACs preferentially associate with MyoD (and possibly other muscle bHLH proteins),30,31 while class II HDACs are dedicated repressors of MEF2-dependent transcription.32 These interactions prevent the local hyperacetylation on the regulatory elements of muscle genes. During muscle differentiation, HDACs are displaced from muscle bHLH and MEF2 proteins by distinct mechanisms,33 thereby allowing productive interactions with acetyltransferases p300 and PCAF.34 Histone methyltransferases belonging to the SET-domain containing families are other critical mediators of muscle gene repression in myoblasts. For instance, Suv39 h1-mediated methylation of H3 lysine 9 and Polycomb-mediated trimethylation of H3 lysine 27 are essential epigenetic modifications that restrict the temporal expression of muscle genes in myoblasts.35,36 The enzymatic component of the Polycomb complex (PcG), the H3-K27 methyltransferase Ezh2, is recruited to the chromatin of muscle regulatory regions via interaction with YY1 binding site and its interaction with HDAC1 forms a repressive complex. At the onset of differentiation, the downregulation of Ezh2 and HDAC1 proteins, and the replacement of YY1 with SRF, allows the binding of MyoD and the recruitment of the positive co-activators, to form a productive transcriptosome.36

These epigenetic marks of transcription silencing are erased by differentiation-induced events that are still unknown, but presumably involve specific demetylases and/or histone exchange. Simultaneously, the acetyltransferases p300/CBP,3740 PCAF,41 the arginine-methyltransferase CARM1,42 and PRMT5,43 the ATPase-dependent SWI/SNF chromatin-remodeling complexes44,45 and the functional homologue of the Trithorax group—the MML compelx containing the histone methyltransferase Ash2L,46 are recruited via interactions with MRFs and MEF2 proteins, thereby endowing the myogenic transcriptosome with the enzymatic activities necessary to modify the chromatin structure and initiate the transcription of target genes.21

An essential step to activate gene transcription relates to the remodelling of the chromatin within the nucleosome. Different chromatin-remodelling complexes have been characterized with an enzymatic (ATP-ase) activity, which produces changes in chromatin structure by altering DNA-histone contacts within the nucleosome.47 The mammalian SWI/SNF is a multiprotein chromatin-remodelling complex composed by at least 10 elements. SWI/SNF remodels the chromatin thereby imparting discrete configurations that are either permissive or repressive for transcription.47 Indeed, in addition to the transcriptional activator functions, SWI/SNF can repress transcription in concert with pRb and HDAC.48 All subunits of the SWI/SNF are well conserved from yeast to humans, and structural analysis of their protein domains suggests specific functional properties. Two distinct SWI/SNF complexes have been described, each characterized by the presence of a unique subunit: BAF (BAF250) or PBAF (BAF180). BAF can contain either BRG1 or BRM as the core motor subunit, whereas PBAF only contains BRG1. The central core subunits BRG1 and BRM contain an ATPase domain and a bromodomain—a recognition motif found in several transcriptional co-regulators that bind acetylated lysines residues in histone tails or in other proteins.47

The ability of SWI/SNF complex to activate or repress gene transcription depends on the signalling activated in a specific context. For instance, activation of the p38 signalling (and in particular of p38 alpha and beta kinases) promotes the recruitment of SWI/SNF on muscle promoters and directs the formation of a multiprotein complexes that contains MyoD, MEF2 and acetyltransferases in combination with the IGF1-activated AKT 1/2 kinases.49 By contrast, the p38 signalling mediated by p38 gamma represses the differentiation program by promoting the association of MyoD with the histone methyltransferase, KMT1A, which catalyzes H3-K9 methylation.50 While these signalling have been detected and characterized in satellite cells and muscle cell lines and are therefore operating during regeneration, the signalling that control the chromatin-modifying complexes during development is still obscure.

DNA methylation is another major epigenetic modifications that occurs at the DNA level, and is typically involved in the control of gene expression during development. Methylation occurs predominantly at the symmetrical dinucleotide CpG. One striking example of the importance of DNA methylation in the control of skeletal myogenesis is provided by the regulation of MyoD expression. MyoD is selectively expressed in skeletal muscle cells, and its expression in non-muscle cells is prevented by DNA methylation. In fact, demethylating agents can induce MyoD transcription and myogenic conversion in non-muscle cells.51 Recent evidence indicates a further complexity in the regulation of MyoD promoter by epigenetic events. The presence of the histone variant H1b bound to the homeoprotein Msx1 induces repressive chromatin on the regulatory element of MyoD. A histone exchange H1b-H3.3 establishes the epigenetic memory conductive for transcription of MyoD in muscle cells.52

An interesting link between MyoD acetylation, DNA methylation and gene repression during developmental skeletal myogenesis is offered by the recent identification of the Dnmt3-associated protein Rp58 (also known as Zfp238) as downstream target of acetylated MyoD. By day 11.5 p.c. MyoD promotes the expression of RP58 in somitic muscle progenitors, and RP58-mediated repression of the MRF inhibitors Id2 and 3 provides an indirect feed-forward circuit that amplifies the myogenic program.53

Regulation of skeletal myogenesis by miRNA.

Recent studies have shown the importance of small regulatory non-coding RNA (miRNAs, SiRNAs and rasiRNAs) as specific post-transcriptional regulators of gene expression during development.

MicroRNA (miRNAs) are short (20–24 nt-long) non-coding RNAs that regulate negatively gene expression by post-transcriptional mechanisms—e.g., through the degradation of target mRNA or translational repression of target mRNA.54 miRNA-mediated fine-tuning of the expression of target mRNAs works in concert with transcriptional regulatory processes to control the expression of many developmental processes, including skeletal myogenesis.55 miRNAs are transcribed by RNA polymerase II as long primiRNAs, which are cleaved into ∼70 nucleotide hairpin RNA by the Drosha protein complex at the nuclear level, to generate pre-miRNA. Pre-miRNAs are subsequently exported to the cytoplasm by Exportin-5-mediated process and cytosolic cleavage of miRNAs by Dicer generates mature forms that are incorporated into the RNA-induced silencing complexes (RISC). miRNAs target RISC to specific mRNAs with complementary sequences typically located in the 3′ untranslated regions (UTRs).56,57

miRNA are important developmental regulators during embryogenesis. 58 A number of miRNAs is induced during myogenesis and potential targets of microRNAs are genes controlling myoblast proliferation and differentiation.59 The fundamental role played by miRNAs during mouse development is indicated by the finding that a conditional knockout of the miRNA-processing enzyme Dicer in skeletal muscle results in decreased skeletal muscle mass and the formation of myofibers with abnormal morphology.60,61

Individual miRNAs have been shown to regulate skeletal myogenesis in developing embryos and during adult life. Interestingly, in many instances miRNAs regulate muscle gene expression, either positively or negatively, by targeting chromatin-modifying enzymes, thereby illustrating the importance of the functional interactions between components of different epigenetic machineries into a unique network.

Notable examples of interaction between miRNAs and epigenetic regulators of gene transcription is provided by miR1-mediated downregulation of HDAC4,62—which inhibits MEF2-activated gene transcription—and miR-133alpha-mediated repression of SRF62—which contributes to displace Polycomb-associated inhibitory complexes on the chromatin at the regulatory sequences of muscle genes.36 Thus, miR1 promotes and miR-133a inhibits myogenesis. Since miR-1 and miR-133a are co-expressed in skeletal muscle cells, as single bicistronic transcripts, which are regulated by upstream regions bound by MyoD and myogenin,6265 the opposing effects of these co-regulated miRNAs on muscle differentiation reveal the existance of negative and positive regulatory networks governing skeletal myogenesis. The function of miR-1 and miR-133 appears evolutionary conserved, as they control muscle gene expression and sarcomeric actin organization in zebrafish.66

Another interplay between miRNAs and chromatin regulators consist of the miR-26a- and miR-214-mediated repression of the expression of Polycomb group (PcG) Ezh2 methyltransferase, during skeletal myogenesis. In undifferentiated myoblasts, the Polycomb group (PcG) proteins Suz12 and Ezh2 repress miR-214 transcription; however, at the onset of differentiation an initial induction of miR-214 is determined by the transcriptional down-regulation of Ezh2, and by the concomitant recruitment of MyoD and myogenin on the regulatory sequences of miRNA-214.67 Elevated levels of miR-214 target the 3′ UTR of Ezh2, thus further reducing the Ezh2 protein levels and promoting the expression of muscle genes.67 Consistently, mice with genetic ablation of the miR-199a/214 regions within the Dnm3 locus die within a month of birth and displayed several abnormalities, including skeletal and muscle defects.68 At later stages of muscle differentiation, miR-26a is induced and targets Ezh2 to eliminate almost completely its expression.69 Similarly, in undifferentiated myoblasts, miR-29 expression is silenced by the transcription factor YY1 and Polycomb proteins, and miR-29 expression is induced by MEF2 and SRF during muscle differentiation. YY1 is a primary target of miR-29. And in rhabdomyosarcoma (RD) cells, which escape terminal differentiaiton, elevated levels of YY1 promote Polycomb recruitment to miR-29 regulatory regions, to silencing miRNA-29 and maintain RD cells in the undifferentiated state.70

The miRNA-mediated repression of EzH2 during skeletal myogenesis is an example of how miRNA can indirectly affect an epigenetic mark (H3-K27 tri-methylation) on the chromatin of muscle genes.

Other miRNAs regulate muscle gene transcription during skeletal myogenesis. miR206, is induced by MyoD and Myogenin and promotes muscle differentiation by a positivefeedback loop.7173 miR-181 is strongly induced during differentiation of skeletal muscle cells and in regenerating myofibers, and targets the homeobox Hox-A11, which represses MyoD and terminal muscle differentiation.74 miR-27b is expressed in somitic regions from where Pax3 expression is absent, and miR-27b (and a) directly target Pax3 3′UTR. Transgenic animals expressing miR-27b in Pax3-positive cells display a shift from Pax3/7-positive progenitor cells to cells that are myogenin-positive and have entered myogenic differentiation, supporting a miR-27b-dependent mechanism that favors in vivo differentiation of muscle progenitor cells by reducing Pax3.75

Conclusions

The results described above illustrate the reciprocal regulation between chromatin-modifying enzymes and miRNAs in the control of gene expression during skeletal myogenesis. This control warrants the temporal coordination of gene expression in skeletal muscle progenitors, by making available the transcriptional machinery to specific loci in a temporal order. The feedback established by MRFs, chromatin-associated enzymatic complexes and miRNAs well accomplishes this task, by determining the epigenetic conditions toward activating or repressing specific subsets of genes at sequential stages of skeletal myogenesis. For instance, MRF-induced expression of miRNAs that target the components of repressive complexes, such as HDAC and Polycomb members, establishes the optimal conditions for de-repression of MRF-target genes at the onset of muscle differentiation, thereby amplyfing a process that ultimately leads to the formation of differentiated myofibers—see

The deconvolution of these networks will provide an important paradigm to understand the epigenetic regulation of tissue and organ development and regeneration, and will help to decipher the molecular pathways that control the bidirectional transition from stem cells to differentiated phenotypes—a current challenge in regenerative medicine.

Figure 2.

Figure 2

Likewise, we predict that a similar circuit might regulate the availability and composition of chromatin-modifying complexes that promote muscle gene transcription during myoblast differentiation.

Footnotes

References

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