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 adn others) redirect 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 activate transcription, MyoD requires the assistance of other interacting partners such as the p300/CBP and PCAf coactivators. We have previously reported that p300 and PCAF are nodal coactivators of the muscle specific transcription factor MyoD. MyoD is acetylated by PCAF and this results in an increased DNA-binding and transcriptional activity. Acetylation and deacetylation are in a dynamic equilibrium and our studies have identified a role for the histone deacetylases (HDACs) in controlling muscle differentiation. To uncover the molecular mechanisms and the effectors that mediate the HDACs activity, we have used small molecules to inhibit the enzymatic activity of HDACs in skeletal muscle cells and performed microarray temporal profiling. Furthermore, prompted by the observation that the redox state fluctuates in skeletal muscle in response to modification of oxygen tension and glucose uptake, we have analyzed the role of the NAD+-dependent deacetylase Sir2 in controlling muscle gene expression.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Arthritis, Musculoskeletal, Skin Dis
Department
Type
DUNS #
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Country
United States
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Sartorelli, Vittorio; Puri, Pier Lorenzo (2018) Shaping Gene Expression by Landscaping Chromatin Architecture: Lessons from a Master. Mol Cell 71:375-388
Puri, Pier Lorenzo; Sartorelli, Vittorio (2010) HDACs and sirtuins: targets for new pharmacological interventions in human diseases. Pharmacol Res 62:1-2
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Fulco, Marcella; Cen, Yana; Zhao, Po et al. (2008) Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell 14:661-73
Fulco, Marcella; Sartorelli, Vittorio (2008) Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tissues. Cell Cycle 7:3669-79
Di Padova, Monica; Caretti, Giuseppina; Zhao, Po et al. (2007) MyoD acetylation influences temporal patterns of skeletal muscle gene expression. J Biol Chem 282:37650-9
Caretti, Giuseppina; Lei, Elissa P; Sartorelli, Vittorio (2007) The DEAD-box p68/p72 proteins and the noncoding RNA steroid receptor activator SRA: eclectic regulators of disparate biological functions. Cell Cycle 6:1172-6
Bakay, Marina; Wang, Zuyi; Melcon, Gisela et al. (2006) Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. Brain 129:996-1013
Minetti, G C; Colussi, C; Adami, R et al. (2006) Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat Med 12:1147-50
Zhao, Po; Caretti, Giuseppina; Mitchell, Stephanie et al. (2006) Fgfr4 is required for effective muscle regeneration in vivo. Delineation of a MyoD-Tead2-Fgfr4 transcriptional pathway. J Biol Chem 281:429-38

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