Chromatin Remodeling and the Control of Gene Expression

Abstract

Biochemical and genetic findings accumulated over the past decade have established that the condensation of eukaryotic DNA in chromatin functions not only to constrain the genome within the boundaries of the cell nucleus but also to suppress gene activity in a general manner. This genetic repression extends from the level of the nucleosome, the primary unit of chromatin organization, where coiling of DNA on the surface of the nucleosome core particle impedes access to the transcriptional apparatus, to the higher order folding of nucleosome arrays and the organization of silent regions of chromatin (for reviews see Refs. 1van Holde K. Zlatanova J. Arents G. Moudrianakis E. Elgin S.C.R. Chromatin Structure and Gene Expression. Oxford University Press, Oxford, UK1995: 1-26Google Scholar, 2Ramakrishnan V. Annu. Rev. Biophys. Biomol. Struct. 1997; 26: 83-112Crossref PubMed Scopus (132) Google Scholar, 3Pruss D. Hayes J.J. Wolffe A.P. Bioessays. 1995; 17: 161-170Crossref PubMed Google Scholar, 4Grunstein M. Annu. Rev. Cell Biol. 1990; 6: 643-678Crossref PubMed Google Scholar, 5Kornberg R.D. Lorch Y. Annu. Rev. Cell Biol. 1992; 8: 563-589Crossref PubMed Google Scholar, 6Fletcher T.M. Hansen J.C. Crit. Rev. Eukaryotic Gene Expression. 1996; 6: 149-188Crossref PubMed Google Scholar and 105Koshland D. Strunnikov A. Annu. Rev. Cell Biol. 1996; 12: 305-333Crossref Scopus (283) Google Scholar). Chromatin structure is inextricably linked to transcriptional regulation, and recent studies show how chromatin is perturbed so as to facilitate transcription (for reviews see Refs. 7Adams C.C. Workman J.L. Cell. 1993; 72: 305-308Abstract Full Text PDF PubMed Scopus (134) Google Scholar, 8Paranjape S.M. Kamakaka R.T. Kadonaga J.T. Annu. Rev. Biochem. 1994; 63: 265-297Crossref PubMed Google Scholar, 9Kornberg R.D. Lorch Y. Curr. Opin. Cell Biol. 1995; 7: 371-375Crossref PubMed Scopus (95) Google Scholar, 10Felsenfeld G. Cell. 1996; 86: 13-19Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 11Brownell J.E. Allis C.D. Curr. Opin. Genet. Dev. 1996; 6: 176-184Crossref PubMed Scopus (438) Google Scholar, 12Krude T. Elgin S.C.R. Curr. Biol. 1996; 6: 511-515Abstract Full Text Full Text PDF PubMed Google Scholar). Here, we review the substantial advances in the identification of histone acetyltransferases and histone deacetylases, whose opposing activities establish the steady-state level of histone acetylation, and progress in studies of multicomponent systems that require energy for the process of nucleosome disruption.Histone AcetylationSince the early discovery of histone acetylation by Allfrey and colleagues (13Allfrey V.G. Faulkner R. Mirsky A.E. Proc. Natl. Acad. Sci. U. S. A. 1964; 51: 786-794Crossref PubMed Google Scholar), this post-translation modification has been correlated with the processes of transcription and chromatin assembly. Acetylation occurs at specific lysines in the flexible N-terminal histone tails that protrude from the nucleosome surface (11Brownell J.E. Allis C.D. Curr. Opin. Genet. Dev. 1996; 6: 176-184Crossref PubMed Scopus (438) Google Scholar, 14Turner B.M. O'Neil L.P. Semin. Cell Biol. 1995; 6: 229-236Crossref PubMed Google Scholar). Hyperacetylation of histones is associated with transcriptional activity or the potential for activity, whereas histone hypoacetylation is correlated with transcriptionally silent chromatin and heterochromatin. Histone acetylation is also associated with the active deposition and maturation of newly assembled nucleosomes during DNA replication (for reviews see Refs. 14Turner B.M. O'Neil L.P. Semin. Cell Biol. 1995; 6: 229-236Crossref PubMed Google Scholar and 15Loidl P. Chromosoma. 1994; 103: 441-449Crossref PubMed Google Scholar). Acetylation reduces the net positive charge of the histones and weakens interactions with DNA (16Hong L. Schroth G.P. Matthews H.R. Yau P. Bradbury E.M. J. Biol. Chem. 1993; 268: 305-314Abstract Full Text PDF PubMed Google Scholar), inhibits the higher order folding of nucleosome arrays (17Hansen J.C. Wolffe A.P. Biochemistry. 1992; 31: 7977-7988Crossref PubMed Google Scholar, 18Garcia-Ramirez M. Rocchini C. Ausio J. J. Biol. Chem. 1995; 270: 17923-17928Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar), and disrupts specific interactions with nonhistone regulators, as shown for the yeast silencer and repressor proteins Sir3 and Sir4 (19Thompson J.S. Ling X. Grunstein M. Nature. 1994; 369: 245-247Crossref PubMed Scopus (202) Google Scholar, 20Hecht A. Laroche T. Strahl-Bosinger S. Gasser S.M. Grunstein M. Cell. 1995; 80: 583-592Abstract Full Text PDF PubMed Scopus (674) Google Scholar) and Tup-1 (21Edmondson D.G. Smith M.M. Roth S.Y. Genes Dev. 1996; 10: 1247-1259Crossref PubMed Google Scholar).Tetrahymena Histone Acetyltransferase A and Yeast Gcn5In a convergence of biochemical and genetic studies, cloning of the p55 catalytic subunit of Tetrahymena nuclear (A-type) histone acetyltransferase (HAT) 1The abbreviations used are: HAT, histone acetyltransferase; P/CAF, p300/CBP-associated factor; CBP, CREB-binding protein; CREB, cyclic AMP response element binding protein; SAS, something about silencing; MOZ, monocytic leukemia zinc finger; MOF, males absent on the first; TAF, TBP-associated factor; TBP, TATA-binding protein; HDAC, histone deacetylase. revealed substantial sequence identity with yeast Gcn5, previously defined genetically as a transcriptional coactivator (22Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1210) Google Scholar). The catalytic domain of the Gcn5 HAT is required for coactivator function in vivo, providing a genetic link between histone modification and transcriptional activation (23Candau R. Zhou J.X. Allis C.D. Berger S.L. EMBO J. 1997; 16: 555-565Crossref PubMed Scopus (174) Google Scholar). As a human GCN5 homolog has been identified, this HAT is likely to be widely conserved (24Candau R. Moore P.A. Wang L. Barlev N. Ying C.Y. Rosen C.A. Berger S.L. Mol. Cell. Biol. 1996; 16: 593-602Crossref PubMed Scopus (154) Google Scholar, 25Wang L. Mizzen C. Ying C. Candau R. Barlev N. Brownell J. Allis C.D. Berger S.L. Mol. Cell. Biol. 1997; 17: 519-527Crossref PubMed Google Scholar). Bacterially expressed yeast Gcn5 protein acetylates free histone H3 strongly at lysine 14 and histone H4 weakly at lysines 8 and 16 (26Kuo M.-H. Brownell J.E. Sobel R.E. Ranalli T.A. Cook R.G. Edmondson D.G. Roth S.Y. Allis C.D. Nature. 1996; 383: 269-272Crossref PubMed Scopus (480) Google Scholar). However, unlike the native HAT A enzyme, recombinant Gcn5 cannot acetylate nucleosomal histones, implying that other subunits in the complex must influence its activity on chromatin. Genetic and biochemical studies reveal at least two interacting proteins, Ada2 and Ada3, that form a complex with Gcn5 (23Candau R. Zhou J.X. Allis C.D. Berger S.L. EMBO J. 1997; 16: 555-565Crossref PubMed Scopus (174) Google Scholar,27Marcus G.A. Silverman N. Berger S.L. Horiuchi J. Guarente L. EMBO J. 1994; 13: 4807-4815Crossref PubMed Scopus (234) Google Scholar, 28Horiuchi J. Silverman N. Marcus G.A. Guarente L. Mol. Cell. Biol. 1995; 15: 1203-1209Crossref PubMed Google Scholar, 29Georgakopoulos T. Gounalaki N. Thireos G. Mol. Gen. Genet. 1995; 246: 723-728Crossref PubMed Scopus (53) Google Scholar). Binding of Ada2 to the activation domains of the transcriptional activators VP16 and Gcn4 in vitro suggests a mechanism by which promoter targeting of Gcn5 might be achieved (30Silverman N. Agapite J. Guarente L. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11665-11668Crossref PubMed Scopus (96) Google Scholar,31Barlev N.A. Candau R. Wang L. Darpino P. Silverman N. Berger S.L. J. Biol. Chem. 1995; 270: 19337-19344Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar).P/CAF, p300/CBP, SAS, MOZ, and MOFAn increasing number of putative or demonstrated histone acetyltransferases have emerged in the past year. P/CAF (p300/CBP-associated factor) is a novel histone acetyltransferase isolated on the basis of sequence similarity to human and yeast Gcn5 (32Yang X.-J. Ogryzko V.V. Nishizawa J. Howard B.H. Nakayani Y. Nature. 1996; 382: 319-324Crossref PubMed Scopus (1283) Google Scholar), which interacts with the highly related transcriptional coactivators p300/CBP. Like Gcn5, recombinant P/CAF has intrinsic HAT activity for free histones H3 and H4, but unlike Gcn5, P/CAF is also able to acetylate nucleosomal histone H3. p300/CBP (CREB-binding protein) is itself a histone acetyltransferase with no resemblance in sequence to the other acetyltransferases (33Ogryzko V. Schiltz R.L. Russanova V. Howard B.H. Nakatani Y. Cell. 1996; 87: 953-959Abstract Full Text Full Text PDF PubMed Scopus (2274) Google Scholar, 106Bannister A.J. Kouzarides T. Nature. 1996; 384: 641-643Crossref PubMed Scopus (1480) Google Scholar). The bacterially expressed p300/CBP protein is unique among HAT polypeptides in that it can acetylate all four core histones free in solution or when complexed in the nucleosome; acetylation on histone H4 occurs at lysines 5, 8, 12, and 16, the same positions that are subject to acetylation in vivo (32Yang X.-J. Ogryzko V.V. Nishizawa J. Howard B.H. Nakayani Y. Nature. 1996; 382: 319-324Crossref PubMed Scopus (1283) Google Scholar). p300 and CBP are known to physically interact with numerous transcription factors activated by signaling cascades, including CREB, c-Jun/v-Jun, Fos, and nuclear hormone receptors, and are also targets for the E1A oncoprotein (for a review see Ref. 34Janknecht R. Hunter T. Nature. 1996; 383: 22-23Crossref PubMed Scopus (337) Google Scholar). Whether histones are substrates of p300 in vivo remains to be determined.The yeast SAS, human MOZ and Tip60, and fly MOF proteins constitute a different class of putative acetyltransferases, characterized by a ∼300-amino acid region of significant similarity that contains a C2CH zinc finger motif and a subregion similar to HATs and other acetyltransferases (35Reifsnyder C. Lowell J. Clarke A. Pillus L. Nat. Genet. 1996; 14: 42-49Crossref PubMed Scopus (234) Google Scholar, 36Borrow J. Stanton Jr., V.P. Andresen J.M. Becher R. Behm F.G. Chaganti R.S.K. Civin C.I. Disteche C. Dube I. Frischauf A.M. Horsman D. Mitelman F. Volinia S. Watmore A.E. Housman D.E. Nat. Genet. 1996; 14: 33-41Crossref PubMed Scopus (609) Google Scholar, 37Kamine J. Elangovan B. Subramanian T. Coleman D. Chjnnadurai G. Virology. 1996; 216: 357-366Crossref PubMed Scopus (237) Google Scholar, 38Hilfiker A. Hilfiker-Kleiner D. Pannuti A. Lucchesi J. EMBO J. 1997; 16: 2054-2060Crossref PubMed Scopus (353) Google Scholar). The biochemical properties or substrate specificities of these proteins involved in silencing (SAS), transcriptional activation (Tip60), leukemogenesis (MOZ), and dosage compensation (MOF) have not yet been described. Interestingly, recurrent translocation in a subtype of acute myeloid leukemia generates a novel fusion of MOZ with CBP, suggesting that the aberrant acetylation of histones or other chromosomal proteins could mediate leukemogenesis (36Borrow J. Stanton Jr., V.P. Andresen J.M. Becher R. Behm F.G. Chaganti R.S.K. Civin C.I. Disteche C. Dube I. Frischauf A.M. Horsman D. Mitelman F. Volinia S. Watmore A.E. Housman D.E. Nat. Genet. 1996; 14: 33-41Crossref PubMed Scopus (609) Google Scholar).TAF250TFIID, the general transcription factor complex of TBP (TATA-binding protein) and the associated TAF proteins, has been found to contain a HAT activity. Unique among the various TAFs, TAFII250 alone or in the TFIID complex has both a serine kinase activity selective for RAP74 (a subunit of TFIIF) and a HAT activity (39Dikstein R. Ruppert S. Tjian R. Cell. 1996; 84: 781-790Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 40Mizzen C.A. Yang X.-J. Kokubo T. Brownell J.E. Bannister A.J. Owen-Hughes T. Workman J.L. Berger S.L. Kouzarides T. Nakatani Y. Aliis C.D. Cell. 1996; 87: 1261-1270Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar). Like Gcn5, TAFII250 preferentially acetylates free histone H3 over H4 and has little or no activity on nucleosomal histones (40Mizzen C.A. Yang X.-J. Kokubo T. Brownell J.E. Bannister A.J. Owen-Hughes T. Workman J.L. Berger S.L. Kouzarides T. Nakatani Y. Aliis C.D. Cell. 1996; 87: 1261-1270Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar). The domain of TAFII250 responsible for HAT activity maps to the central, conserved region and shows no obvious sequence similarity to other HATs. The finding of HAT activity in TAFII250 implies that TFIID could contribute toward destabilizing nucleosomes over core promoter elements, although the physiological substrates of the HAT activity remain to be determined. TFIID may possess yet an another capacity for assisting nucleosome disorder. Portions of several TAFs (DrosophilaTAFII42 and TAFII62) adopt a histone octamer-like substructure that might be employed as a histone octamer-like substructure, which could serve as a competitor for DNA binding with the core histones (41Hoffman A. Chiang C.-M. Oelgeschlager T. Xie X. Burley S.K. Nakatani Y. Roeder R. Nature. 1996; 380: 356-359Crossref PubMed Scopus (157) Google Scholar, 42Nakatani Y. Bagby S. Ikura M. J . Biol. Chem. 1996; 271: 6575-6578Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 43Xie X. Kokubo T. Cohen S.L. Mirza U.A. Hoffman A. Chait B.T. Roeder R. Nakatani Y. Burley S.K. Nature. 1996; 380: 316-322Crossref PubMed Scopus (223) Google Scholar).Histone DeacetylasesIn parallel with the identification of HAT enzymes, studies of histone deacetylase (HDAC) enzymes in human, yeast, andDrosophila have also advanced significantly. Affinity chromatography with the ligand trapoxin, a high affinity, irreversible inhibitor, resulted in the purification and cloning of a human deacetylase (44Tauton J. Hassig C.A. Schreiber S.L. Science. 1996; 272: 408-411Crossref PubMed Scopus (1456) Google Scholar) composed of a catalytic subunit, HD-1, renamed HDAC1 (45Hassig C.A. Fleischer T.C. Billin A.N. Schreibert S.L. Ayer D.E. Cell. 1997; 89: 341-347Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar), and a tightly associated WD repeat protein, RbAp48. The sequence of the HDAC1 showed very strong sequence identity to yeast Rpd3, previously identified genetically to be necessary for full repression and activation of a subset of genes (46Vidal M. Gaber R. Mol. Cell. Biol. 1991; 11: 6317-6327Crossref PubMed Google Scholar). There are five members of theRPD3 family in yeast, two of which (HDA1 andRPD3) are components of the major histone deacetylase activities, which fractionate as 350-kDa (HDA) and 600-kDa (HDB) complexes (47Carmen A.A. Rundlett S.E. Grunstein M. J. Biol. Chem. 1996; 271: 15837-15844Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 48Rundlett S.E. Carmen A.A. Kobayashi R. Bavykin S. Turner B. Grunstein M. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14503-14508Crossref PubMed Scopus (495) Google Scholar).As anticipated from the catalytic properties of the encoded proteins, deletions of the HDA1 and RPD3 genes strongly reduce HDA and HDB activities, leading to hyperacetylation of histones H3 and H4 in vivo. However, the phenotypes of these deletions are somewhat surprising, as they increase repression rather than increase activation of telomeric loci (48Rundlett S.E. Carmen A.A. Kobayashi R. Bavykin S. Turner B. Grunstein M. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14503-14508Crossref PubMed Scopus (495) Google Scholar). Similarly, mutation of a Drosophila homolog of RPD3 displays an enhancer of position effect variegation phenotype, suggesting that loss of wild-type Drosophila RPD3 function as a histone deacetylase leads to increased gene silencing (49De Rubertis F. Kadosh D. Henchoz S. Pauli D. Reuter G. Struhl K. Spierer P. Nature. 1996; 384: 589-591Crossref PubMed Scopus (190) Google Scholar). These findings may perhaps be related to the acetylation of histone H4 at lysine 12, which is required for transcriptional silencing in yeast (50Braunstein M. Sorbel R.E. Allis C.D. Turner B.M. Broach J.R. Mol. Cell. Biol. 1996; 16: 4349-4356Crossref PubMed Google Scholar) and which is also associated with heterochromatin in Drosophila (51Turner B.M. Birley A.J. Lavender J. Cell. 1992; 69: 375-384Abstract Full Text PDF PubMed Google Scholar), despite net hypoacetylation.More in line with the anticipated involvement of histone deacetylases in transcriptional repression is the physical association of the heteromeric Mad (Mxi1)/Max DNA binding repressors involved in controlling cell proliferation and differentiation with mammalian RPD3 homologs and with Sin3, a conserved transcriptional co-repressor genetically linked to yeast Rpd3 (45Hassig C.A. Fleischer T.C. Billin A.N. Schreibert S.L. Ayer D.E. Cell. 1997; 89: 341-347Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar, 52Laherty C.D. Yang W.M. Sun J.M. Davie J.R. Seto E. Eisenman R.N. Cell. 1997; 89: 349-356Abstract Full Text Full Text PDF PubMed Scopus (815) Google Scholar). Immunopurification studies also reveal additional, novel polypeptides associated with Sin3 and histone deacetylase in human cell extracts (54Zhang Y. Iranti R. Erdjument-Bromage H. Tempst P. Reinberg D. Cell. 1997; 89: 357-364Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar). YY1, a mammalian sequence-specific transcription factor that can serve as a repressor binds directly to histone deacetylase (55Yang W.M. Inouye C. Zeng Y. Bearss D. Seto E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 12845-12850Crossref PubMed Scopus (465) Google Scholar), and NCoR and SMRT, co-repressors for nuclear hormone receptors, interact with complexes containing mammalian Sin3 and histone deacetylase (53Alland L. Muhle R. Hou H. Potes J. Chin L. Schreiber-Agus N. DePinho D. Nature. 1997; 387: 49-55Crossref PubMed Google Scholar, 56Heinzel T. Lavinsky R.M. Mullen T.M. Soderstrom M. et al.Nature. 1997; 387: 43-48Crossref PubMed Google Scholar, 57Nagy L. Kao H.Y. Chakravarti D. Lin R.J. Hassig C.A. Ayer D.E. Schreiber S.L. Evans R.M. Cell. 1997; 89: 373-380Abstract Full Text Full Text PDF PubMed Scopus (1069) Google Scholar). Repression of meiotic genes by the yeast Ume6 protein also involves recruitment of a complex containing Sin3 and Rpd3 (58Kadosh D. Struhl K. Cell. 1997; 89: 365-371Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar). This literal explosion of new data provides strong support for a model of gene-specific repression by the recruitment of multicomponent, histone deacetylase complexes to target promoters.PerspectivesWith the emergence of so many new modifiers of chromatin structure comes a long list of outstanding questions that should provide fertile ground for future study. What is the fate of nucleosomal histones during the remodeling process? Are histones partly or fully evicted from DNA, and how might a residual structure promote interactions between DNA binding regulators (102Chavez S. Beato M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2885-2890Crossref PubMed Scopus (67) Google Scholar)? Do nucleosomes that are intrinsically unstable or hyperstable due to the structure of DNA have different requirements for disruption? What roles in chromatin remodeling are performed by architectural DNA-binding proteins such as LEF-1, HMG I(Y), and others (103Werner M.H. Burley S.K. Cell. 1997; 88: 733-736Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) and by the RNA polymerase complex itself (104Gaudreau L. Schmid A. Blaschke D. Ptashne M. Horz W. Cell. 1997; 89: 55-62Abstract Full Text Full Text PDF PubMed Google Scholar)? Which chromatin modifiers are brought into play for a particular gene and at which step of the activation process: the binding of upstream regulators, assembly of the preinitiation complex, initiation, elongation, or termination? Are ATP-dependent remodeling activities recruited to specific chromosomal sites, or do they diffuse along the chromatin fiber, creating transient windows of opportunity for other factors? When histone-modifying enzymes are recruited by DNA-binding factors, what is the spread of the modification along a nucleosome array, and how is the modification contained? Are the activities of the histone acetyltransferases and histone deacetylases hierarchically integrated with the SWI/SNF2 family of remodeling machines? How does nucleosome remodeling impact on higher order chromatin folding, or is it regulated by higher order chromatin folding? Answers to these and other questions will surely yield important insights not only for the control of gene expression but also for diverse aspects of chromosome biology. Biochemical and genetic findings accumulated over the past decade have established that the condensation of eukaryotic DNA in chromatin functions not only to constrain the genome within the boundaries of the cell nucleus but also to suppress gene activity in a general manner. This genetic repression extends from the level of the nucleosome, the primary unit of chromatin organization, where coiling of DNA on the surface of the nucleosome core particle impedes access to the transcriptional apparatus, to the higher order folding of nucleosome arrays and the organization of silent regions of chromatin (for reviews see Refs. 1van Holde K. Zlatanova J. Arents G. Moudrianakis E. Elgin S.C.R. Chromatin Structure and Gene Expression. Oxford University Press, Oxford, UK1995: 1-26Google Scholar, 2Ramakrishnan V. Annu. Rev. Biophys. Biomol. Struct. 1997; 26: 83-112Crossref PubMed Scopus (132) Google Scholar, 3Pruss D. Hayes J.J. Wolffe A.P. Bioessays. 1995; 17: 161-170Crossref PubMed Google Scholar, 4Grunstein M. Annu. Rev. Cell Biol. 1990; 6: 643-678Crossref PubMed Google Scholar, 5Kornberg R.D. Lorch Y. Annu. Rev. Cell Biol. 1992; 8: 563-589Crossref PubMed Google Scholar, 6Fletcher T.M. Hansen J.C. Crit. Rev. Eukaryotic Gene Expression. 1996; 6: 149-188Crossref PubMed Google Scholar and 105Koshland D. Strunnikov A. Annu. Rev. Cell Biol. 1996; 12: 305-333Crossref Scopus (283) Google Scholar). Chromatin structure is inextricably linked to transcriptional regulation, and recent studies show how chromatin is perturbed so as to facilitate transcription (for reviews see Refs. 7Adams C.C. Workman J.L. Cell. 1993; 72: 305-308Abstract Full Text PDF PubMed Scopus (134) Google Scholar, 8Paranjape S.M. Kamakaka R.T. Kadonaga J.T. Annu. Rev. Biochem. 1994; 63: 265-297Crossref PubMed Google Scholar, 9Kornberg R.D. Lorch Y. Curr. Opin. Cell Biol. 1995; 7: 371-375Crossref PubMed Scopus (95) Google Scholar, 10Felsenfeld G. Cell. 1996; 86: 13-19Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 11Brownell J.E. Allis C.D. Curr. Opin. Genet. Dev. 1996; 6: 176-184Crossref PubMed Scopus (438) Google Scholar, 12Krude T. Elgin S.C.R. Curr. Biol. 1996; 6: 511-515Abstract Full Text Full Text PDF PubMed Google Scholar). Here, we review the substantial advances in the identification of histone acetyltransferases and histone deacetylases, whose opposing activities establish the steady-state level of histone acetylation, and progress in studies of multicomponent systems that require energy for the process of nucleosome disruption. Histone AcetylationSince the early discovery of histone acetylation by Allfrey and colleagues (13Allfrey V.G. Faulkner R. Mirsky A.E. Proc. Natl. Acad. Sci. U. S. A. 1964; 51: 786-794Crossref PubMed Google Scholar), this post-translation modification has been correlated with the processes of transcription and chromatin assembly. Acetylation occurs at specific lysines in the flexible N-terminal histone tails that protrude from the nucleosome surface (11Brownell J.E. Allis C.D. Curr. Opin. Genet. Dev. 1996; 6: 176-184Crossref PubMed Scopus (438) Google Scholar, 14Turner B.M. O'Neil L.P. Semin. Cell Biol. 1995; 6: 229-236Crossref PubMed Google Scholar). Hyperacetylation of histones is associated with transcriptional activity or the potential for activity, whereas histone hypoacetylation is correlated with transcriptionally silent chromatin and heterochromatin. Histone acetylation is also associated with the active deposition and maturation of newly assembled nucleosomes during DNA replication (for reviews see Refs. 14Turner B.M. O'Neil L.P. Semin. Cell Biol. 1995; 6: 229-236Crossref PubMed Google Scholar and 15Loidl P. Chromosoma. 1994; 103: 441-449Crossref PubMed Google Scholar). Acetylation reduces the net positive charge of the histones and weakens interactions with DNA (16Hong L. Schroth G.P. Matthews H.R. Yau P. Bradbury E.M. J. Biol. Chem. 1993; 268: 305-314Abstract Full Text PDF PubMed Google Scholar), inhibits the higher order folding of nucleosome arrays (17Hansen J.C. Wolffe A.P. Biochemistry. 1992; 31: 7977-7988Crossref PubMed Google Scholar, 18Garcia-Ramirez M. Rocchini C. Ausio J. J. Biol. Chem. 1995; 270: 17923-17928Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar), and disrupts specific interactions with nonhistone regulators, as shown for the yeast silencer and repressor proteins Sir3 and Sir4 (19Thompson J.S. Ling X. Grunstein M. Nature. 1994; 369: 245-247Crossref PubMed Scopus (202) Google Scholar, 20Hecht A. Laroche T. Strahl-Bosinger S. Gasser S.M. Grunstein M. Cell. 1995; 80: 583-592Abstract Full Text PDF PubMed Scopus (674) Google Scholar) and Tup-1 (21Edmondson D.G. Smith M.M. Roth S.Y. Genes Dev. 1996; 10: 1247-1259Crossref PubMed Google Scholar). Since the early discovery of histone acetylation by Allfrey and colleagues (13Allfrey V.G. Faulkner R. Mirsky A.E. Proc. Natl. Acad. Sci. U. S. A. 1964; 51: 786-794Crossref PubMed Google Scholar), this post-translation modification has been correlated with the processes of transcription and chromatin assembly. Acetylation occurs at specific lysines in the flexible N-terminal histone tails that protrude from the nucleosome surface (11Brownell J.E. Allis C.D. Curr. Opin. Genet. Dev. 1996; 6: 176-184Crossref PubMed Scopus (438) Google Scholar, 14Turner B.M. O'Neil L.P. Semin. Cell Biol. 1995; 6: 229-236Crossref PubMed Google Scholar). Hyperacetylation of histones is associated with transcriptional activity or the potential for activity, whereas histone hypoacetylation is correlated with transcriptionally silent chromatin and heterochromatin. Histone acetylation is also associated with the active deposition and maturation of newly assembled nucleosomes during DNA replication (for reviews see Refs. 14Turner B.M. O'Neil L.P. Semin. Cell Biol. 1995; 6: 229-236Crossref PubMed Google Scholar and 15Loidl P. Chromosoma. 1994; 103: 441-449Crossref PubMed Google Scholar). Acetylation reduces the net positive charge of the histones and weakens interactions with DNA (16Hong L. Schroth G.P. Matthews H.R. Yau P. Bradbury E.M. J. Biol. Chem. 1993; 268: 305-314Abstract Full Text PDF PubMed Google Scholar), inhibits the higher order folding of nucleosome arrays (17Hansen J.C. Wolffe A.P. Biochemistry. 1992; 31: 7977-7988Crossref PubMed Google Scholar, 18Garcia-Ramirez M. Rocchini C. Ausio J. J. Biol. Chem. 1995; 270: 17923-17928Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar), and disrupts specific interactions with nonhistone regulators, as shown for the yeast silencer and repressor proteins Sir3 and Sir4 (19Thompson J.S. Ling X. Grunstein M. Nature. 1994; 369: 245-247Crossref PubMed Scopus (202) Google Scholar, 20Hecht A. Laroche T. Strahl-Bosinger S. Gasser S.M. Grunstein M. Cell. 1995; 80: 583-592Abstract Full Text PDF PubMed Scopus (674) Google Scholar) and Tup-1 (21Edmondson D.G. Smith M.M. Roth S.Y. Genes Dev. 1996; 10: 1247-1259Crossref PubMed Google Scholar). Tetrahymena Histone Acetyltransferase A and Yeast Gcn5In a convergence of biochemical and genetic studies, cloning of the p55 catalytic subunit of Tetrahymena nuclear (A-type) histone acetyltransferase (HAT) 1The abbreviations used are: HAT, histone acetyltransferase; P/CAF, p300/CBP-associated factor; CBP, CREB-binding protein; CREB, cyclic AMP response element binding protein; SAS, something about silencing; MOZ, monocytic leukemia zinc finger; MOF, males absent on the first; TAF, TBP-associated factor; TBP, TATA-binding protein; HDAC, histone deacetylase. revealed substantial sequence identity with yeast Gcn5, previously defined genetically as a transcriptional coactivator (22Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1210) Google Scholar). The catalytic domain of the Gcn5 HAT is required for coactivator function in vivo, providing a genetic link between histone modification and transcriptional activation (23Candau R. Zhou J.X. Allis C.D. Berger S.L. EMBO J. 1997; 16: 555-565Crossref PubMed Scopus (174) Google Scholar). As a human GCN5 homolog has been identified, this HAT is likely to be widely conserved (24Candau R. Moore P.A. Wang L. Barlev N. Ying C.Y. Rosen C.A. Berger S.L. Mol. Cell. Biol. 1996; 16: 593-602Crossref PubMed Scopus (154) Google Scholar, 25Wang L. Mizzen C. Ying C. Candau R. Barlev N. Brownell J. Allis C.D. Berger S.L. Mol. Cell. Biol. 1997; 17: 519-527Crossref PubMed Google Scholar). Bacterially expressed yeast Gcn5 protein acetylates free histone H3 strongly at lysine 14 and histone H4 weakly at lysines 8 and 16 (26Kuo M.-H. Brownell J.E. Sobel R.E. Ranalli T.A. Cook R.G. Edmondson D.G. Roth S.Y. Allis C.D. Nature. 1996; 383: 269-272Crossref PubMed Scopus (480) Google Scholar). However, unlike the native HAT A enzyme, recombinant Gcn5 cannot acetylate nucleosomal histones, implying that other subunits in the complex must influence its activity on chromatin. Genetic and biochemical studies reveal at least two interacting proteins, Ada2 and Ada3, that form a