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Molecular and Cellular Biology, October 2005, p. 8456-8464, Vol. 25, No. 19
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.19.8456-8464.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulation of MEF2 by Histone Deacetylase 4- and SIRT1 Deacetylase-Mediated Lysine Modifications

Xuan Zhao,1 Thomas Sternsdorf,2 Timothy A. Bolger,1 Ronald M. Evans,2 and Tso-Pang Yao1*

Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710,1 Gene Expression Laboratory, The Salk Institute for Biological Studies, and Howard Hughes Medical Institute, La Jolla, California 920372

Received 28 February 2005/ Returned for modification 11 April 2005/ Accepted 6 June 2005

The class II deacetylase histone deacetylase 4 (HDAC4) negatively regulates the transcription factor MEF2. HDAC4 is believed to repress MEF2 transcriptional activity by binding to MEF2 and catalyzing local histone deacetylation. Here we report that HDAC4 also controls MEF2 by a novel SUMO E3 ligase activity. We show that HDAC4 interacts with the SUMO E2 conjugating enzyme Ubc9 and is itself sumoylated. The overexpression of HDAC4 leads to prominent MEF2 sumoylation in vivo, whereas recombinant HDAC4 stimulates MEF2 sumoylation in a reconstituted system in vitro. Importantly, HDAC4 promotes sumoylation on a lysine residue that is also subject to acetylation by a MEF2 coactivator, the acetyltransferase CBP, suggesting a possible interplay between acetylation and sumoylation in regulating MEF2 activity. Indeed, MEF2 acetylation is correlated with MEF2 activation and dynamically induced upon muscle cell differentiation, while sumoylation inhibits MEF2 transcriptional activity. Unexpectedly, we found that HDAC4 does not function as a MEF2 deacetylase. Instead, the NAD+-dependent deacetylase SIRT1 can potently induce MEF2 deacetylation. Our studies reveal a novel regulation of MEF2 transcriptional activity by two distinct classes of deacetylases that affect MEF2 sumoylation and acetylation.

* Corresponding author. Mailing address: Department of Pharmacology and Cancer Biology, P.O. Box 3813, Duke University Medical Center, Durham, NC 27710. Phone: (919) 613-8654. Fax: (919) 668-3954. E-mail: yao00001{at}mc.duke.edu.

Molecular and Cellular Biology, October 2005, p. 8456-8464, Vol. 25, No. 19
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.19.8456-8464.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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