Differential role of p300 and CBP acetyltransferase during myogenesis: p300 acts upstream of MyoD and Myf5

Studies in tissue culture cells have implicated p300 and CBP acetyltransferases in myogenic regulatory factor (MRF) mediated transcription and terminal differentiation of skeletal muscle cells. However, in vivo data placing p300 and CBP on myogenic differentiation pathways are not yet available. In this report we provide genetic evidence that p300 but not CBP acetyltransferase (AT) activity is required for myogenesis in the mouse and in embryonic stem (ES) cells. A fraction of embryos carrying a single p300 AT‐ deficient allele exhibit impaired MRF expression, delayed terminal differentiation and a reduced muscle mass. In mouse embryos lacking p300 protein, Myf‐5 induction is severely attenuated. Similarly, ES cells homozygous for a p300 AT or a p300 null mutation fail to activate Myf5 and MyoD transcription efficiently, while Pax3, acting genetically upstream of these MRFs, is expressed. In contrast, ES cells lacking CBP AT activity express MyoD and Myf5 and undergo myogenic differentiation. These data reveal a specific requirement for p300 and its AT activity in the induction of MRF gene expression and myogenic cell fate determination in vivo.

[1]  D. Livingston,et al.  Interaction and functional collaboration of p300/CBP and bHLH proteins in muscle and B-cell differentiation. , 1996, Genes & development.

[2]  M. Buckingham Skeletal muscle formation in vertebrates. , 2001, Current opinion in genetics & development.

[3]  H. Masuya,et al.  Abnormal skeletal patterning in embryos lacking a single Cbp allele: a partial similarity with Rubinstein-Taybi syndrome. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[4]  N. L. La Thangue,et al.  p300/CBP proteins: HATs for transcriptional bridges and scaffolds. , 2001, Journal of cell science.

[5]  Y. Capetanaki,et al.  Cytoskeletal control of myogenesis: a desmin null mutation blocks the myogenic pathway during embryonic stem cell differentiation. , 1995, Developmental biology.

[6]  David Newsome,et al.  Gene Dosage–Dependent Embryonic Development and Proliferation Defects in Mice Lacking the Transcriptional Integrator p300 , 1998, Cell.

[7]  C. Mello,et al.  A CBP/p300 homolog specifies multiple differentiation pathways in Caenorhabditis elegans. , 1998, Genes & development.

[8]  G. Cossu,et al.  Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5. , 1998, Development.

[9]  I. Talianidis,et al.  Acetylation regulates transcription factor activity at multiple levels. , 2000, Molecular cell.

[10]  M. Rudnicki,et al.  The molecular regulation of myogenesis , 2000, Clinical genetics.

[11]  T. Braun,et al.  Myf‐5 and myoD genes are activated in distinct mesenchymal stem cells and determine different skeletal muscle cell lineages. , 1996, The EMBO journal.

[12]  D. Livingston,et al.  Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. , 2000, Genes & development.

[13]  L. Kedes,et al.  Differential roles of p300 and PCAF acetyltransferases in muscle differentiation. , 1997, Molecular cell.

[14]  T. Braun,et al.  Myf-5 Revisited Loss of Early Myotome Formation Does Not Lead to a Rib Phenotype in Homozygous Myf-5 Mutant Mice , 2000, Cell.

[15]  A. Giordano,et al.  p300 is required for MyoD‐dependent cell cycle arrest and muscle‐specific gene transcription , 1997, The EMBO journal.

[16]  D. Wilkinson In situ hybridization: a practical approach , 1998 .

[17]  R. Kingston,et al.  Cooperation between Complexes that Regulate Chromatin Structure and Transcription , 2002, Cell.

[18]  S. Koester,et al.  Ectopic Pax-3 Activates MyoD and Myf-5 Expression in Embryonic Mesoderm and Neural Tissue , 1997, Cell.

[19]  H. Arnold,et al.  Pax-3 is required for the development of limb muscles: a possible role for the migration of dermomyotomal muscle progenitor cells. , 1994, Development.

[20]  K. Guan,et al.  In vitro differentiation of embryonic stem cells and analysis of cellular phenotypes. , 2001, Methods in molecular biology.

[21]  A. Harel-Bellan,et al.  CREB-binding Protein/p300 Activates MyoD by Acetylation* , 2000, Journal of Biological Chemistry.

[22]  M. Gassmann,et al.  Embryoid Bodies: An In Vitro Model of Mouse Embryogenesis , 2000, Experimental physiology.

[23]  C. Emerson,et al.  Muscle determination: Another key player in myogenesis? , 1997, Current Biology.

[24]  A. Harel-Bellan,et al.  CBP/p300 and muscle differentiation: no HAT, no muscle , 2001, The EMBO journal.

[25]  B. Howard,et al.  The Transcriptional Coactivators p300 and CBP Are Histone Acetyltransferases , 1996, Cell.

[26]  G. Condorelli,et al.  Human p300 Protein Is a Coactivator for the Transcription Factor MyoD (*) , 1996, The Journal of Biological Chemistry.

[27]  S. Ishii,et al.  Extensive brain hemorrhage and embryonic lethality in a mouse null mutant of CREB-binding protein , 2000, Mechanisms of Development.

[28]  D. Livingston,et al.  Distinct roles of the co-activators p300 and CBP in retinoic-acid-induced F9-cell differentiation , 1998, Nature.

[29]  C. Emerson,et al.  Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification. , 2002, Genes & development.

[30]  S. Tajbakhsh,et al.  The birth of muscle progenitor cells in the mouse: spatiotemporal considerations. , 2000, Current topics in developmental biology.

[31]  Andrew L. Kung,et al.  Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[32]  E. Olson,et al.  Control of muscle development by dueling HATs and HDACs. , 2001, Current opinion in genetics & development.

[33]  J. Rehg,et al.  A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis , 2002, Nature.

[34]  A. Lassar,et al.  The origin of skeletal muscle stem cells in the embryo and the adult. , 2001, Current opinion in cell biology.

[35]  C. Hui,et al.  Developmentally regulated expression of the transcriptional cofactors/histone acetyltransferases CBP and p300 during mouse embryogenesis. , 1999, The International journal of developmental biology.

[36]  L. Kedes,et al.  Acetylation of MyoD directed by PCAF is necessary for the execution of the muscle program. , 1999, Molecular cell.

[37]  A M Wobus,et al.  Muscle cell differentiation of embryonic stem cells reflects myogenesis in vivo: developmentally regulated expression of myogenic determination genes and functional expression of ionic currents. , 1994, Developmental biology.

[38]  Andrew J. Bannister,et al.  The CBP co-activator is a histone acetyltransferase , 1996, Nature.

[39]  S. Ishii,et al.  Drosophila CBP is required for dorsal–dependent twist gene expression , 1997, Nature Genetics.

[40]  G. Cossu,et al.  Redefining the Genetic Hierarchies Controlling Skeletal Myogenesis: Pax-3 and Myf-5 Act Upstream of MyoD , 1997, Cell.

[41]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[42]  C. Dani,et al.  Compactin enhances osteogenesis in murine embryonic stem cells. , 2001, Biochemical and biophysical research communications.

[43]  N. Shikama,et al.  Essential function of p300 acetyltransferase activity in heart, lung and small intestine formation , 2003, The EMBO journal.

[44]  V. Ogryzko,et al.  Regulation of activity of the transcription factor GATA-1 by acetylation , 1998, Nature.

[45]  T. Braun,et al.  ES-cells carrying two inactivated myf-5 alleles form skeletal muscle cells: activation of an alternative myf-5-independent differentiation pathway. , 1994, Developmental biology.

[46]  G. Blobel,et al.  CREB-Binding Protein Acetylates Hematopoietic Transcription Factor GATA-1 at Functionally Important Sites , 1999, Molecular and Cellular Biology.

[47]  Wei Gu,et al.  Activation of p53 Sequence-Specific DNA Binding by Acetylation of the p53 C-Terminal Domain , 1997, Cell.

[48]  K. Ozato,et al.  Distinct but overlapping roles of histone acetylase PCAF and of the closely related PCAF-B/GCN5 in mouse embryogenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[49]  L. Kedes,et al.  Class I histone deacetylases sequentially interact with MyoD and pRb during skeletal myogenesis. , 2001, Molecular cell.

[50]  C. Tabin,et al.  Developmental regulation of somite derivatives: muscle, cartilage and tendon. , 2002, Current opinion in genetics & development.

[51]  A. Wolffe,et al.  Acetylation of general transcription factors by histone acetyltransferases , 1997, Current Biology.

[52]  H. Arnold,et al.  Muscle differentiation: more complexity to the network of myogenic regulators. , 1998, Current opinion in genetics & development.

[53]  Yvonne A. Evrard,et al.  Loss of Gcn5l2 leads to increased apoptosis and mesodermal defects during mouse development , 2000, Nature Genetics.

[54]  H. Arnold,et al.  Early expression of the myogenic regulatory gene, myf-5, in precursor cells of skeletal muscle in the mouse embryo. , 1991, Development.

[55]  K. Rajewsky,et al.  A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. , 1995, Nucleic acids research.

[56]  R. Goodman,et al.  CBP/p300 in cell growth, transformation, and development. , 2000, Genes & development.

[57]  L. Kedes,et al.  Molecular mechanisms of myogenic coactivation by p300: direct interaction with the activation domain of MyoD and with the MADS box of MEF2C , 1997, Molecular and cellular biology.

[58]  C. Dani,et al.  Impaired ossification in mice lacking the transcription factor Sp3 , 2001, Mechanisms of Development.

[59]  L. Bordoli,et al.  Functional analysis of the p300 acetyltransferase domain: the PHD finger of p300 but not of CBP is dispensable for enzymatic activity. , 2001, Nucleic acids research.

[60]  N. Shiama The p300/CBP family: integrating signals with transcription factors and chromatin. , 1997, Trends in cell biology.

[61]  L. Bordoli,et al.  Plant orthologs of p300/CBP: conservation of a core domain in metazoan p300/CBP acetyltransferase-related proteins. , 2001, Nucleic acids research.