The specification of skeletal muscle cells, starting from totipotent stem cells, lies at the core of skeletal myogenesis. During this process, the genome of the progenitor muscle cells is modified to ensure that stable - if not irreversible - distinctions are made between genes not to be expressed and genes whose expression is or will be required. MyoD is a transcriptional activator required for muscle-specific gene expression. Expression of exogenous MyoD in numerous terminally differentiated cell lineages (neurons, adipocytes, skin cells, chondrocytes and others) redirects their fates towards the skeletal muscle phenotype. Furthermore, MyoD - and the related Myf-5 protein - is essential for the formation of skeletal muscles in the animal. In order to regulate transcription, MyoD recruits chromatin and histone modifying enzymes. Specification and maintenance of committed, yet undifferentiated, muscle precursors are the result of a fine balance between gene activation and repression. Genes to be expressed in terminally differentiated cells are actively repressed in muscle precursors. Ezh2, the subunit conferring methyltransferase activity to the Polycomb Repressive Complex 2 (PRC2), occupies and methylates histones located at regulatory regions of muscle-specific genes not expressed in muscle precursors. Once differentation ensues, Ezh2 binding is lost and histone methylation is erased, resulting in transcriptional activation. In addition to methylation-demethylation, other histone modifications are associated with muscle gene expression. Acetylation and deacetylation are in a dynamic equilibrium, and our studies have identified a role for several histone deacetylases (HDACs) in controlling muscle differentiation. We have used small molecules to modulate the enzymatic activity of several HDACs in skeletal muscle cells. Pharmacological modulation of the HDACs was found to ameliorate the morphology and function of mouse dystrophic muscles. With the aim of contributing to a better understanding of the mechanisms that regulate gene expression in physiological and pathological conditions, we will continue to identify and functionally characterize molecules that cause histone and chromatin modifications and regulate proliferation, differentiation, and regeneration of skeletal muscle cells.

Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2013
Total Cost
$1,556,700
Indirect Cost
Name
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Department
Type
DUNS #
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Feng, Xuesong; Juan, Aster H; Wang, Hongjun A et al. (2016) Polycomb Ezh2 controls the fate of GABAergic neurons in the embryonic cerebellum. Development 143:1971-80
Juan, Aster H; Sartorelli, Vittorio (2016) S6K1ing to ResTOR Adipogenesis with Polycomb. Mol Cell 62:325-6
Dell'Orso, Stefania; Wang, A Hongjun; Shih, Han-Yu et al. (2016) The Histone Variant MacroH2A1.2 Is Necessary for the Activation of Muscle Enhancers and Recruitment of the Transcription Factor Pbx1. Cell Rep 14:1156-68
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Mammen, Andrew L; Sartorelli, Vittorio (2015) IL-6 Blockade as a Therapeutic Approach for Duchenne Muscular Dystrophy. EBioMedicine 2:274-5
Jin, Qihuang; Wang, Chaochen; Kuang, Xianghong et al. (2014) Gcn5 and PCAF regulate PPARγ and Prdm16 expression to facilitate brown adipogenesis. Mol Cell Biol 34:3746-53
Mousavi, Kambiz; Zare, Hossein; Koulnis, Miroslav et al. (2014) The emerging roles of eRNAs in transcriptional regulatory networks. RNA Biol 11:106-10
Zare, Hossein; Khodursky, Arkady; Sartorelli, Vittorio (2014) An evolutionarily biased distribution of miRNA sites toward regulatory genes with high promoter-driven intrinsic transcriptional noise. BMC Evol Biol 14:74

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