Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2.
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.
Grégoire
Serge
S
Molecular Oncology Group, Royal Victoria Hospital, McGill University Health Center, 687 Pine Avenue West, Montréal, Quebec H3A 1A1, Canada.
Xiao
Lin
L
Nie
Jianyun
J
Zhang
Xiaohong
X
Xu
Minghong
M
Li
Jiarong
J
Wong
Jiemin
J
Seto
Edward
E
Yang
Xiang-Jiao
XJ
D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D064326:MEF2 Transcription Factors; D051379:Mice; D008957:Models, Genetic; D024510:Muscle Development / Q000235:genetics; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; D000099186:Histone Deacetylase 3
D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D012097:Repressor Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; D000099186:Histone Deacetylase 3; C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse