Overlapping but Distinct Patterns of Histone Acetylation by the Human Coactivators p300 and PCAF within Nucleosomal Substrates*

A number of transcriptional coactivators possess intrinsic histone acetylase activity, providing a direct link between hyperacetylated chromatin and transcriptional activation. We have determined the core histone residues acetylated in vitro by recombinant p300 and PCAF within mononucleosomes. p300 specifically acetylates all sites of histones H2A and H2B known to be acetylated in bulk chromatin in vivo but preferentially acetylates lysines 14 and 18 of histone H3 and lysines 5 and 8 of histone H4. PCAF primarily acetylates lysine 14 of H3 but also less efficiently acetylates lysine 8 of H4. PCAF in its native form, which is present in a stable multimeric protein complex lacking p300/CBP, primarily acetylates H3 to a monoacetylated form, suggesting that PCAF-associated polypeptides do not alter the substrate specificity. These distinct patterns of acetylation by the p300 and PCAF may contribute to their differential roles in transcriptional regulation.

[1]  P. Becker,et al.  Chromatin-remodeling factors: machines that regulate? , 1998, Current opinion in cell biology.

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

[3]  C. Allis,et al.  Histone acetyltransferase activity of yeast Gcn5p is required for the activation of target genes in vivo. , 1998, Genes & development.

[4]  F. Ballantyne,et al.  A polymorphism maintained by opposite patterns of parasitism and predation , 1997, Nature.

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

[6]  C. Allis,et al.  Non-random acetylation of histone H4 by a cytoplasmic histone acetyltransferase as determined by novel methodology. , 1994, The Journal of biological chemistry.

[7]  B. Howard,et al.  A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A , 1996, Nature.

[8]  T. Richmond,et al.  Crystal structure of the nucleosome core particle at 2.8 Å resolution , 1997, Nature.

[9]  Jun Qin,et al.  Histone-like TAFs within the PCAF Histone Acetylase Complex , 1998, Cell.

[10]  B. Wang,et al.  The nucleosomal core histone octamer at 3.1 A resolution: a tripartite protein assembly and a left-handed superhelix. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[11]  P. Sautière,et al.  Patterns of histone acetylation. , 1990, European journal of biochemistry.

[12]  K. Struhl.  Histone acetylation and transcriptional regulatory mechanisms. , 1998, Genes & development.

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

[14]  C. Allis,et al.  Conservation of deposition-related acetylation sites in newly synthesized histones H3 and H4. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. T. Kadonaga,et al.  Role of nucleosomal cores and histone H1 in regulation of transcription by RNA polymerase II. , 1991, Science.

[16]  Y. Shi,et al.  Adenovirus E1A downregulates cJun- and JunB-mediated transcription by targeting their coactivator p300 , 1996, Molecular and cellular biology.

[17]  M. Roberge,et al.  Nucleosome arrays inhibit both initiation and elongation of transcripts by bacteriophage T7 RNA polymerase. , 1992, Journal of molecular biology.

[18]  Andrew J. Bannister,et al.  CBP‐induced stimulation of c‐Fos activity is abrogated by E1A. , 1995, The EMBO journal.

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

[20]  C. Glass,et al.  Signal-specific co-activator domain requirements for Pit-1 activation , 1998, Nature.

[21]  R. Goodman,et al.  Adenoviral ElA-associated protein p300 as a functional homologue of the transcriptional co-activator CBP , 1995, Nature.

[22]  C. Allis,et al.  An activity gel assay detects a single, catalytically active histone acetyltransferase subunit in Tetrahymena macronuclei. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Grunstein.  Histone acetylation in chromatin structure and transcription , 1997, Nature.

[24]  P. Kaufman.  Nucleosome assembly: the CAF and the HAT. , 1996, Current opinion in cell biology.

[25]  C. Allis,et al.  Steroid receptor coactivator-1 is a histone acetyltransferase , 1997, Nature.

[26]  R. Evans,et al.  Nuclear Receptor Coactivator ACTR Is a Novel Histone Acetyltransferase and Forms a Multimeric Activation Complex with P/CAF and CBP/p300 , 1997, Cell.

[27]  S. Berger,et al.  Critical residues for histone acetylation by Gcn5, functioning in Ada and SAGA complexes, are also required for transcriptional function in vivo. , 1998, Genes & development.

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

[29]  W. Bonner,et al.  Histone 2A, a heteromorphous family of eight protein species. , 1980, Biochemistry.

[30]  P. Grant,et al.  Transcriptional activators direct histone acetyltransferase complexes to nucleosomes , 1998, Nature.

[31]  C. Allis,et al.  ESA1 is a histone acetyltransferase that is essential for growth in yeast. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[32]  C. Allis,et al.  Special HATs for special occasions: linking histone acetylation to chromatin assembly and gene activation. , 1996, Current opinion in genetics & development.

[33]  C. D. Allis,et al.  Linking histone acetylation to transcriptional regulation , 1998, Cellular and Molecular Life Sciences CMLS.

[34]  C. Allis,et al.  Tetrahymena Histone Acetyltransferase A: A Homolog to Yeast Gcn5p Linking Histone Acetylation to Gene Activation , 1996, Cell.

[35]  Andrew J. Bannister,et al.  The TAFII250 Subunit of TFIID Has Histone Acetyltransferase Activity , 1996, Cell.

[36]  R Ohba,et al.  Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. , 1997, Genes & development.

[37]  C. Allis,et al.  Histone Acetylation and Chromatin Assembly: A Single Escort, Multiple Dances? , 1996, Cell.

[38]  K. Sakaguchi,et al.  DNA damage activates p53 through a phosphorylation-acetylation cascade. , 1998, Genes & development.

[39]  Thorsten Heinzel,et al.  A CBP Integrator Complex Mediates Transcriptional Activation and AP-1 Inhibition by Nuclear Receptors , 1996, Cell.

[40]  W. Sellers,et al.  E1A-associated p300 and CREB-associated CBP belong to a conserved family of coactivators , 1994, Cell.

[41]  C. Glass,et al.  Transcription factor-specific requirements for coactivators and their acetyltransferase functions. , 1998, Science.

[42]  Carl Wu.  Chromatin Remodeling and the Control of Gene Expression* , 1997, The Journal of Biological Chemistry.