A dynamic role for HDAC7 in MEF2-mediated muscle differentiation.
The overlapping expression profile of MEF2 and the class-II histone deacetylase, HDAC7, led us to investigate the functional interaction and relationship between these regulatory proteins. HDAC7 expression inhibits the activity of MEF2 (-A, -C, and -D), and in contrast MyoD and Myogenin activities are not affected. Glutathione S-transferase pulldown and immunoprecipitation demonstrate that the repression mechanism involves direct interactions between MEF2 proteins and HDAC7 and is associated with the ability of MEF2 to interact with the N-terminal 121 amino acids of HDAC7 that encode repression domain 1. The MADS domain of MEF2 mediates the direct interaction of MEF2 with HDAC7. MEF2 inhibition by HDAC7 is dependent on the N-terminal repression domain and surprisingly does not involve the C-terminal deacetylase domain. HDAC7 interacts with CtBP and other class-I and -II HDACs suggesting that silencing of MEF2 activity involves corepressor recruitment. Furthermore, we show that induction of muscle differentiation by serum withdrawal leads to the translocation of HDAC7 from the nucleus into the cytoplasm. This work demonstrates that HDAC7 regulates the function of MEF2 proteins and suggests that this class-II HDAC regulates this important transcriptional (and pathophysiological) target in heart and muscle tissue. The nucleocytoplasmic trafficking of HDAC7 and other class-II HDACs during myogenesis provides an ideal mechanism for the regulation of HDAC targets during mammalian development and differentiation.
University of Queensland, Institute for Molecular Bioscience, Centre for Molecular and Cellular Biology, Ritchie Research Laboratories, B402A, St. Lucia 4072, Queensland, Australia.
U
U
Dressel
P J
PJ
Bailey
S C
SC
Wang
M
M
Downes
R M
RM
Evans
G E
GE
Muscat
D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology* / Q000502:physiology*; D018006:Myogenic Regulatory Factors; D021381:Protein Transport; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; D014157:Transcription Factors; C400300:HDAC4 protein, human; C543273:HDAC7 protein, human; C498618:Hdac5 protein, mouse; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases