Regulation of MEF2 by Histone Deacetylase 4- and SIRT1 Deacetylase-Mediated Lysine Modifications
Open accessAbstract
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.
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HDAC4 belongs to the SUMO E3 ligase family and can directly SUMOylate IκBα, AR, LXRα, and MEF2.
“Additionally, HDAC4 belongs to the SUMO E3 ligase family and can directly SUMOylate IκBα, AR, LXRα, and MEF217–20.”
From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [18]
Sirt1 and HDAC3, but not HDAC4 or -5, efficiently deacetylate MEF2D, contributing to MEF2D-dependent transcriptional repression.
“More recently, it has been shown that both Sirt1 (28) and HDAC3 (29), and not HDAC4 or -5, efficiently deacetylate MEF2D, thus contributing to MEF2Ddependent transcriptional repression.”
From Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases (2007) · cites this paper as [28]
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- Authors
- Zhao, X., Sternsdorf, T., Bolger, T. A., Evans, R. M., & Yao, T.-P.
- Affiliations
- Duke University (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Yao, Tso-Pang
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-10-01
- Volume
- 25
- Issue
- 19
- Pages
- 8456-8464
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1265742
- OpenAlex
- W2133015492
- Cited by
- 264
- References
- 45
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 7 · 2023: 1 · 2022: 5 · 2021: 11 · 2020: 10 · 2019: 11 · 2018: 10 · 2017: 12 · 2016: 16 · 2015: 18 · 2014: 13 · 2013: 18 · 2012: 15
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- MEF2, HDAC4, SIRT1, SUMOylation, acetylation, lysine modification, SUMO E3 ligase, Ubc9, CBP, transcriptional regulation, muscle cell differentiation, histone deacetylation
- MeSH terms
- Acetylation, Amino Acid Sequence, Animals, Cell Differentiation, Cell Line, DNA, Fibroblasts, Gene Expression Regulation, Genetic Vectors, Histone Deacetylases, Humans, Luciferases, Lysine, Models, Biological, Molecular Sequence Data, Mutation, Plasmids, Recombinant Proteins, Repressor Proteins, Transcription, Genetic, Transfection, Blotting, Western, Protein Structure, Tertiary, Myogenic Regulatory Factors, Small Ubiquitin-Related Modifier Proteins, Sirtuins, Ubiquitin-Protein Ligases, Immunoprecipitation, Mice, Sirtuin 1, MEF2 Transcription Factors
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