Forcales SV, Puri PLSignaling to the chromatin during skeletal myogenesis: novel targets for pharmacological modulation of gene expression. Semin Cell Dev Biol 16: 596-611

Laboratory of Gene Expression, Dulbecco Telethon Institute (DTI) at Fondazione A. Cesalpino, ICBTE, San Raffaele Biomedical Science Park of Rome, Rome, Italy.
Seminars in Cell and Developmental Biology (Impact Factor: 6.27). 08/2005; 16(4-5):596-611. DOI: 10.1016/j.semcdb.2005.07.005
Source: PubMed


Cellular differentiation entails an extensive reprogramming of the genome toward the expression of discrete subsets of genes, which establish the tissue-specific phenotype. This program is achieved by epigenetic marks of the chromatin at particular loci, and is regulated by environmental cues, such as soluble factors and cell-to-cell interactions. How the intracellular cascades convert the myriad of external stimuli into the nuclear information necessary to reprogram the genome toward specific responses is a question of biological and medical interest. The elucidation of the signaling converting cues from outside the cells into chromatin modifications at individual promoters holds the promise to unveil the targets for selective pharmacological interventions to modulate gene expression for therapeutic purposes. Enhancing muscle regeneration and preventing muscle breakdown are important goals in the therapy of muscular diseases, cancer-associated cachexia and aging-associated sarcopenia. We will summarize the recent progress of our knowledge of the regulation of gene expression by intracellular cascades elicited by external cues during skeletal myogenesis. And will illustrate the potential importance of targeting the chromatin signaling in regenerative medicine--e.g. to boost muscle regeneration.

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Available from: Sonia Forcales
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    • "The muscle regulatory factors that drive myogenic differentiation have been well studied; however, the mechanisms that control their expression are poorly understood. It has been suggested that epigenetic regulation and post-translation modifications of histones in particular play a critical role in skeletal muscle differentiation [4], [5]. "
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    ABSTRACT: Heterochromatin protein 1 (HP1) is an essential heterochromatin-associated protein typically involved in the epigenetic regulation of gene silencing. However, recent reports have demonstrated that HP1 can also activate gene expression in certain contexts including differentiation. To explore the role of each of the three mammalian HP1 family members (α, β and γ) in skeletal muscle, their expression was individually disrupted in differentiating skeletal myocytes. Among the three isoforms of HP1, HP1α was specifically required for myogenic gene expression in myoblasts only. Knockdown of HP1α led to a defect in transcription of skeletal muscle-specific genes including Lbx1, MyoD and myogenin. HP1α binds to the genomic region of myogenic genes and depletion of HP1α results in a paradoxical increase in histone H3 lysine 9 trimethylation (H3K9me3) at these sites. JHDM3A, a H3K9 demethylase also binds to myogenic gene's genomic regions in myoblasts in a HP1α-dependent manner. JHDM3A interacts with HP1α and knockdown of JHDM3A in myoblasts recapitulates the decreased myogenic gene transcription seen with HP1α depletion. These results propose a novel mechanism for HP1α-dependent gene activation by interacting with the demethylase JHDM3A and that HP1α is required for maintenance of myogenic gene expression in myoblasts.
    Full-text · Article · Mar 2013 · PLoS ONE
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    • "Determination of the myogenic lineage and differentiation of skeletal muscle cells are precisely orchestrated by the concerted action of muscle-specific transcription factors (MRFs) and chromatin modifier enzymes such as nuclear histone acetyltransferases (HATs) and deacetylases (HDACs) (1–4), as well as factors regulating the methylation states of various muscle-specific promoter genes. Although histone acetylation is a common marker of transcriptionally active chromatin, histone methylation is associated with both gene activation and repression, depending on the site where it occurs. "
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    ABSTRACT: The proliferation and differentiation of muscle precursor cells require myogenic regulatory factors and chromatin modifiers whose concerted action dynamically regulates access to DNA and allows reprogramming of cells towards terminal differentiation. Type 2 deiodinase (D2), the thyroid hormone (TH)-activating enzyme, is sharply upregulated during myoblast differentiation, whereas type 3 deiodinase (D3), the TH-inactivating enzyme, is downregulated. The molecular determinants controlling synchronized D2 and D3 expression in muscle differentiation are completely unknown. Here, we report that the histone H3 demethylating enzyme (LSD-1) is essential for transcriptional induction of D2 and repression of D3. LSD-1 relieves the repressive marks (H3-K9me2-3) on the Dio2 promoter and the activation marks (H3-K4me2-3) on the Dio3 promoter. LSD-1 silencing impairs the D2 surge in skeletal muscle differentiation while inducing D3 expression thereby leading to a global decrease in intracellular TH production. Furthermore, endogenous LSD-1 interacts with FoxO3a, and abrogation of FoxO3-DNA binding compromises the ability of LSD-1 to induce D2. Our data reveal a novel epigenetic control of reciprocal deiodinases expression and provide a molecular mechanism by which LSD-1, through the opposite regulation of D2 and D3 expression, acts as a molecular switch that dynamically finely tunes the cellular needs of active TH during myogenesis.
    Full-text · Article · Feb 2013 · Nucleic Acids Research
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    • "Studies have also shown that upon myotube differentiation, widespread chromatin remodeling occurs and genes necessary for differentiation are activated while those for proliferation are repressed (Forcales and Puri, 2005; Guasconi and Puri, 2009; McKinsey et al., 2002; Palacios and Puri, 2006; Sartorelli and Caretti, 2005). Since a subset of labeled myotubes enter cell cycle and proliferate in GM, we reasoned that inhibitor mix have a global effect and perturbation of signaling pathways would in turn affect chromatin remodeling thereby facilitating reprogramming of myotubes to their progenitor cells. "
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    ABSTRACT: Muscle regeneration declines with aging and myopathies, and reprogramming of differentiated muscle cells to their progenitors can serve as a robust source of therapeutic cells. Here, we used the Cre-Lox method to specifically label postmitotic primary multinucleated myotubes and then utilized small molecule inhibitors of tyrosine phosphatases and apoptosis to dedifferentiate these myotubes into proliferating myogenic cells, without gene overexpression. The reprogrammed, fusion competent, muscle precursor cells contributed to muscle regeneration in vitro and in vivo and were unequivocally distinguished from reactivated reserve cells because of the lineage marking method. The small molecule inhibitors downregulated cell cycle inhibitors and chromatin remodeling factors known to promote and maintain the cell fate of myotubes, facilitating cell fate reversal. Our findings enhance understanding of cell-fate determination and create novel therapeutic approaches for improved muscle repair.
    Preview · Article · Sep 2011 · Chemistry & biology
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