This Article Full Text Full Text (PDF) Supplemental material Other Versions of this Article: MCB.00882-06v1 27/4/1280    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grégoire, S. Articles by Yang, X.-J. Search for Related Content PubMed PubMed Citation Articles by Grégoire, S. Articles by Yang, X.-J.

Histone Deacetylase 3 Interacts with and Deacetylates Myocyte Enhancer Factor 2 ^,

Molecular Oncology Group, Department of Medicine, McGill University Health Centre, Montréal, Quebec H3A 1A1, Canada,¹ H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612,² Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030³

Received 17 May 2006/ Returned for modification 26 June 2006/ Accepted 30 November 2006

The myocyte enhancer factor 2 (MEF2) family of transcription factors is not only important for controlling gene expression in normal cellular programs, like muscle differentiation, T-cell apoptosis, neuronal survival, and synaptic differentiation, but has also been linked to cardiac hypertrophy and other pathological conditions. Lysine acetylation has been shown to modulate MEF2 function, but it is not so clear which deacetylase(s) is involved. We report here that treatment of HEK293 cells with trichostatin A or nicotinamide upregulated MEF2D acetylation, suggesting that different deacetylases catalyze the deacetylation. Related to the trichostatin A sensitivity, histone deacetylase 4 (HDAC4) and HDAC5, two known partners of MEF2, exhibited little deacetylase activity towards MEF2D. In contrast, HDAC3 efficiently deacetylated MEF2D in vitro and in vivo. This was specific, since HDAC1, HDAC2, and HDAC8 failed to do so. While HDAC4, HDAC5, HDAC7, and HDAC9 are known to recognize primarily the MEF2-specific domain, we found that HDAC3 interacts directly with the MADS box. In addition, HDAC3 associated with the acetyltransferases p300 and p300/CBP-associated factor (PCAF) to reverse autoacetylation. Furthermore, the nuclear receptor corepressor SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) stimulated the deacetylase activity of HDAC3 towards MEF2 and PCAF. Supporting the physical interaction and deacetylase activity, HDAC3 repressed MEF2-dependent transcription and inhibited myogenesis. These results reveal an unexpected role for HDAC3 and suggest a novel pathway through which MEF2 activity is controlled in vivo.

Published ahead of print on 11 December 2006.

Supplemental material for this article may be found at http://mcb.asm.org/.

^¶ These authors contributed equally to this work.

This article has been cited by other articles:

• Schuetz, A., Min, J., Allali-Hassani, A., Schapira, M., Shuen, M., Loppnau, P., Mazitschek, R., Kwiatkowski, N. P., Lewis, T. A., Maglathin, R. L., McLean, T. H., Bochkarev, A., Plotnikov, A. N., Vedadi, M., Arrowsmith, C. H. (2008). Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deacetylase Activity. J. Biol. Chem. 283: 11355-11363 [Abstract] [Full Text]  
• Angelelli, C., Magli, A., Ferrari, D., Ganassi, M., Matafora, V., Parise, F., Razzini, G., Bachi, A., Ferrari, S., Molinari, S. (2008). Differentiation-dependent lysine 4 acetylation enhances MEF2C binding to DNA in skeletal muscle cells. Nucleic Acids Res 36: 915-928 [Abstract] [Full Text]  
• Di Padova, M., Caretti, G., Zhao, P., Hoffman, E. P., Sartorelli, V. (2007). MyoD Acetylation Influences Temporal Patterns of Skeletal Muscle Gene Expression. J. Biol. Chem. 282: 37650-37659 [Abstract] [Full Text]  
• Reyes-Juarez, J. L., Juarez-Rubi, R., Rodriguez, G., Zarain-Herzberg, A. (2007). Transcriptional Analysis of the Human Cardiac Calsequestrin Gene in Cardiac and Skeletal Myocytes. J. Biol. Chem. 282: 35554-35563 [Abstract] [Full Text]  
• Lahm, A., Paolini, C., Pallaoro, M., Nardi, M. C., Jones, P., Neddermann, P., Sambucini, S., Bottomley, M. J., Lo Surdo, P., Carfi, A., Koch, U., De Francesco, R., Steinkuhler, C., Gallinari, P. (2007). Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl. Acad. Sci. USA 104: 17335-17340 [Abstract] [Full Text]  
• Dokmanovic, M., Clarke, C., Marks, P. A. (2007). Histone Deacetylase Inhibitors: Overview and Perspectives. Mol Cancer Res 5: 981-989 [Abstract] [Full Text]