Class I histone deacetylases sequentially interact with MyoD and pRb during skeletal myogenesis.
We describe a functional and biochemical link between the myogenic activator MyoD, the deacetylase HDAC1, and the tumor suppressor pRb. Interaction of MyoD with HDAC1 in undifferentiated myoblasts mediates repression of muscle-specific gene expression. Prodifferentiation cues, mimicked by serum removal, induce both downregulation of HDAC1 protein and pRb hypophosphorylation. Dephosphorylation of pRb promotes the formation of pRb-HDAC1 complex in differentiated myotubes. pRb-HDAC1 association coincides with disassembling of MyoD-HDAC1 complex, transcriptional activation of muscle-restricted genes, and cellular differentiation of skeletal myoblasts. A single point mutation introduced in the HDAC1 binding domain of pRb compromises its ability to disrupt MyoD-HDAC1 interaction and to promote muscle gene expression. These results suggest that reduced expression of HDAC1 accompanied by its redistribution in alternative nuclear protein complexes is critical for terminal differentiation of skeletal muscle cells.
Puri
P L
PL
Department of Biology, University of California-San Diego, La Jolla, CA 92093, USA. plorenzo@salk.edu
Iezzi
S
S
Stiegler
P
P
Chen
T T
TT
Schiltz
R L
RL
Muscat
G E
GE
Giordano
A
A
Kedes
L
L
Wang
J Y
JY
Sartorelli
V
V
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development* / Q000502:physiology; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism*; D018006:Myogenic Regulatory Factors; D010766:Phosphorylation; D011233:Precipitin Tests; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D017570:MyoD Protein; D018006:Myogenic Regulatory Factors; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases