Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications.
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.
Zhao
Xuan
X
Department of Pharmacology and Cancer Biology, P.O. Box 3813, Duke University Medical Center, Durham, NC 27710, USA.
Sternsdorf
Thomas
T
Bolger
Timothy A
TA
Evans
Ronald M
RM
Yao
Tso-Pang
TP
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D004247:DNA / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008239:Lysine / Q000737:chemistry*; D064326:MEF2 Transcription Factors; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D012097:Repressor Proteins / Q000378:metabolism*; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D011994:Recombinant Proteins; D012097:Repressor Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D004247:DNA; D008156:Luciferases; D044767:Ubiquitin-Protein Ligases; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; C400300:HDAC4 protein, human; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D008239:Lysine