A role for histone deacetylase HDAC1 in modulating the transcriptional activity of MyoD: inhibition of the myogenic program.
The molecular mechanism(s) that are responsible for suppressing MyoD's transcriptional activities in undifferentiated skeletal muscle cells have not yet been determined. We now show that MyoD associates with a histone deacetylase-1 (HDAC1) in these cells and that this interaction is responsible for silencing MyoD-dependent transcription of endogenous p21 as well as muscle-specific genes. Specifically, we present evidence that HDAC1 can bind directly to MyoD and use an acetylated MyoD as a substrate in vitro, whereas a mutant version of HDAC1 (H141A) can not. Further more, this mutant also fails to repress MyoD-mediated transcription in vivo, and unlike wild-type HDAC1 it can not inhibit myogenic conversion, as judged by confocal microscopy. Finally, we show that an endogenous MyoD can be acetylated upon its conversion to a hypophosphorylated state and only when the cells have been induced to differentiate. These results provide for a model which postulates that MyoD may be co-dependent on HDAC1 and P/CAF for temporally controlling its transcriptional activity before and after the differentiation of muscle cells.
Mal
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Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Sturniolo
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Schiltz
R L
RL
Ghosh
M K
MK
Harter
M L
ML
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002461:Cell Line, Transformed; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D051548:Histone Acetyltransferases; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D051548:Histone Acetyltransferases; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D017570:MyoD Protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C110550:HDAC1 protein, human