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Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications.
Mol Cell Biol. 2005 Oct; 25(19):8456-64.MC

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology and Cancer Biology, P.O. Box 3813, Duke University Medical Center, Durham, NC 27710, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

16166628

Citation

Zhao, Xuan, et al. "Regulation of MEF2 By Histone Deacetylase 4- and SIRT1 Deacetylase-mediated Lysine Modifications." Molecular and Cellular Biology, vol. 25, no. 19, 2005, pp. 8456-64.
Zhao X, Sternsdorf T, Bolger TA, et al. Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol Cell Biol. 2005;25(19):8456-64.
Zhao, X., Sternsdorf, T., Bolger, T. A., Evans, R. M., & Yao, T. P. (2005). Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Molecular and Cellular Biology, 25(19), 8456-64.
Zhao X, et al. Regulation of MEF2 By Histone Deacetylase 4- and SIRT1 Deacetylase-mediated Lysine Modifications. Mol Cell Biol. 2005;25(19):8456-64. PubMed PMID: 16166628.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. AU - Zhao,Xuan, AU - Sternsdorf,Thomas, AU - Bolger,Timothy A, AU - Evans,Ronald M, AU - Yao,Tso-Pang, PY - 2005/9/17/pubmed PY - 2005/12/13/medline PY - 2005/9/17/entrez SP - 8456 EP - 64 JF - Molecular and cellular biology JO - Mol. Cell. Biol. VL - 25 IS - 19 N2 - 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. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/16166628/Regulation_of_MEF2_by_histone_deacetylase_4__and_SIRT1_deacetylase_mediated_lysine_modifications_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=16166628 DB - PRIME DP - Unbound Medicine ER -