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Exploiting Histones
Cell, Vol. 86, 365–366, August 9, 1996, Copyright 1996 by Cell Press
Book Review
Exploiting Histones Chromatin Structure and Gene Expression. Edited by Sarah C. R. Elgin. New York: IRL Press. (1995). 224 pp. $105.00, hardcover; $52.00, paperback.
Histones are emerging as substrates for activities controlling transcription. These structural proteins have recently been revealed as targets for post-translational modification (acetylation) by transcriptional adaptors (Brownell et al., Cell 84, 843–851, 1996). Some transcription repressors appear to reverse these modifications or interact directly with the unmodified histones (Hecht et al., Cell 80, 583–592, 1995; Taunton et al., Science 272, 408–410, 1996; Edmondson et al., Genes Dev., 10, 1247–1259, 1996). In addition, the nucleosome seems to structurally resemble TFIID; histones share dimerization motifs with several TATA-binding-protein associated factors, TAFs (Hoffman et al., Nature 380, 356–359). These dramatic discoveries are surely raising interest in histones and chromatin function. However, to understand the relevance of these results, one must appreciate the wealth of information and the unresolved questions regarding chromatin function. By revisiting the advances and conclusions derived in many of the premier systems and approaches used to analyze chromatin structure and function, this book will definitely bring new histone enthusiasts up to speed in this area. The approach taken by the editor strives to emphasize emerging concepts. Each chapter is co-authored by at least two scientists from different research groups. This works extremely well in some chapters, illustrating the similarities and differences in results from quite different experimental systems (for example, Chapter 5). In other chapters, which more closely resemble two distinct half chapters, this has served to provide a continuity of presentation. In addition, the authors have also read and provided comments on chapters other than their own. This has led to a “Discussion” section at the end of each chapter. This section and the preceding “Important Questions” section provides a stark realization of the unresolved issues. Thus this text provides the reader with a realistic mix of substantial advances and unanswered questions. Nucleosome and Chromatin Structure The first two chapters illustrate that a great deal is now known about the structure of the nucleosome core. The histone octamer is formed by the assembly of a series of histone dimers (Chapter 1). Two H3/H4 dimers form a stable tetramer which is then bound on either side by two H2A/H2B dimers. All four core histones share a common three helix structural motif termed the “histone fold” (also found in TFIID, Xie et al., Nature 380, 316–322, 1996), which clasps its dimerization partner over an extended interface. The structured part of the histone octamer interacts with DNA through a pattern of positive
charged amino acids which appear to follow the path of the DNA helix. These interactions and the preferred direction of DNA bending by specific sequences (Chapter 2) undoubtedly contribute to nucleosome positioning in some manner. Chapter 1 also makes it clear that beyond the internal structure of the nucleosome core, details of chromatin structure remain elusive. It describes the historical difficulties in determining higherorder chromatin structure and raises the possibility that the structure of the 30nM fiber is much more irregular than originally hoped.
Activating Chromatin: Remodeling Nucleosome Arrays The experimental systems described in the text provide three examples where transcription factors initiate the remodeling of pre-assembled nucleosome arrays (Chapters 4 and 5). Chapter 5 presents an informative comparison of nucleosome remodeling events which occur in vivo at the mouse mammary tumor virus promoter (MMTV) and the yeast PHO5 promoter upon gene induction. While the exact nature of the chromatin structural transitions remains under investigation it is clear that in both cases these changes are initiated by the binding of inducible transcription factors and occur in the absence of DNA replication. Similarly, the constitutive GAGA factor can initiate a structural transition (i.e. form a DNase 1 hypersensitive site) in pre-assembled nucleosome arrays at Drosophila heat-shock promoters in vitro (Chapter 4). Why then in the “Discussion” section of Chapter 4 do the authors raise the possibility that establishing transcriptional potential may involve DNA replication and chromatin reassembly (described in Chapter 3)? While not described in the text, experiments in synthetic nuclei have shown that a step including DNA replication can convert the transcriptional potential of the developmentally-regulated beta-globin promoter (Barton and Emerson, Genes Dev. 8, 2453–2465, 1994). Moreover, passing through S-phase appears important for establishing repressive heterochromatin structures. “At least one round of replication is required to restore repression to a conditionally de-repressed silent mating type locus” (Chapter 7, page 130). Thus, many important questions remain regarding the potential role of DNA replication in programming gene expression and its relationship to replication-independent mechanisms. Replication-independent transitions in chromatin structure are facilitated by ATP-dependent nucleosome disruption activities. These include the SWI/SNF complex (Chapter 5) and NURF, a distinct nucleosome-remodeling complex (Tsukiyama et al., Cell 83, 1021–1026, 1995). Chapters 4 and 6 illustrate that transcription regulation in chromatin may also occur during elongation. For example, the rate-limiting step in transcription from the Drosophila heat shock promoters is the release of a paused RNA polymerase by heat-shock factor (Chapter 4). RNA polymerase II elongation is inhibited by the presence of nucleosomes on template DNA resulting in increased pausing (Chapter 6). It is not known how
Cell 366
RNA polymerase II eventually transverses nucleosomes. However, a model system utilizing prokaryotic polymerases suggests a spooling mechanism of passing nucleosomes around an RNA polymerase (Chapter 6). Repressing Chromatin: Acting through Histones Chapters 7 and 8 suggest that stable repression is also an “active” process requiring the function of a distinct set of factors. Silencing in yeast and position effect variegation in Drosophila appear to result from the spreading of repressed “heterochromatic” structures. In yeast, silencing initiates at telomeres and silent mating type loci and is linked with both the function of specific repressing factors and the amino terminal regions of the core histones (Chapter 7). Indeed, recent reports illustrate a direct interaction between the Sir3p, Sir4p and Tup1p repressors and the unacetylated amino termini of H3 and H4 (Hecht et al., 1995; Edmondson et al., 1996). These results suggest that these factors interact directly with histone proteins to form a repressed chromatin structure counteracting the function of transcription activators and nucleosome disrupting activities like the SWI/SNF complex. This process is likely to be further modulated by histone acetylation which can reduce the interactions of the histones with the repressor proteins. In this light it is indeed exciting that the transcriptional adaptor protein, GCN5p, functions as a histone acetyltransferase (Brownell et al., 1996) and that the Rpd3p repressor may function as a histone deacetylase (Taunton et al., 1996). The text emphasizes similarities between silencing in yeast, heterochromatic spreading and homeotic silencing in Drosophila (Chapters 7 and 8). Both heterochromatic regions and homeotic silencing result in mitotically stable gene repression which can be mediated through proteins containing chromodomain motifs (i.e HP1 and the Pc-G proteins). It will be interesting to see whether any of these repressors interact directly or indirectly with histones. There are distinct differences in histone acetylation patterns in heterochromatic and euchromatic regions in Drosophila and in mammals. However, in mammals DNA methylation seems the strongest mediator of epigenetic decisions (Chapter 10). Important closely linked mammalian genes can be reciprocally imprinted (e.g. the Igf2 and H19; Chapter 10). Thus the mechanism of imprinting may be more complicated than the formation of open vs. condensed chromatin loops. Indeed, Chapter 9 discusses the challenges in correlating functional domains with the occurrence of DNA sequence elements that appear to bind the nuclear matrix. Functional elements are described that insulate from position effects and block enhancer function (LCRs and insulator elements). The effects of these elements in transgenic animals is striking, yet it remains unclear whether a functional domain represents a structural unit of chromatin.
Summary While not comprehensive, this text covers a substantial amount of important information in this field. The aspect of this book that distinguishes it from other texts on
this topic is that the approach taken by the editor has prevented dogmatic over interpretations. If the reader reaches the end of a chapter not quite understanding how it all fits together, reading the “Important Questions” and “Discussion” sections will likely indicate that neither do the authors. Thus, this text provides the most balanced and realistic view of the status of this field. Jerry L. Workman Department of Biochemistry and Molecular Biology and Center for Gene Regulation The Pennsylvania State University University Park, Pennsylvania 16802 Books Received Abelson, J.N. (1996). Methods in Enzymology Vol 267. Combinatorial Chemistry. Academic Press, San Diego, California. 493 pp. $85.00. Adolph, K.W. (1996). Human Molecular Genetics. Academic Press, Inc.. 500 pp. $85.00. Doolittle, R.F. (1996). Methods in Enzymology Vol 266. Computer Methods for Macromolecular Sequence Analysis. Academic Press, San Diego, California. 711 pp. $110.00. Eun, H.-M. (1996). Enzymology Primer for Recombinant DNA Technology. Academic Press, San Diego, California. 702 pp. $125.00. Fiskum, G. (1996). Neurodegenerative Diseases Molecular and Cellular Mechanisms and Therapeutic Advances. Plenum Publishing, New York. 482 pp. $135.00. Griffin, D.H. (1996). Fungal Physiology. Wiley Publishers, New York. 458 pp. $42.95. Kibbler, C., Mackenzie, D., and Odds, F. (1996). Principles and Practices of Clinical Mycology. Wiley Publishers, New York. 276 pp. $80.00. Paradise, L.J., Bendinelli, M., and Friedman, H. (1996). Enteric Infections and Immunity. Plenum Publishing, New York. 272 pp. $79.50. Rissler, J., Mellon, M. (1996). The Ecological Risks of Engineered Crops. The MIT Press, Cambridge, Massachusetts. 159 pp. $16.95. Smolensky, M.H., and Rensing, L. (1996). Chronobiology International The Journal of Biological and Medical Rhythm Research. Marcel Dekker, Monticello, New York. 80 pp. $175.00. Tomiuk, J., Wohrmann, K., and Sentker, A. (1996). Transgenic Organisms: Biological and Social Implications. Birkhauser, Basel, Switzerland. 263 pp. $83.95. Weinberg, R. A. (1996). Racing to the Beginning of the Road The Search for the Origin of Cancer. Harmony Books, New York, 1996. 270 pp. $27.50. Wirth, J. (1996). Color Atlas of Genetics. Thieme, New York. 411 pp. $29.00.
Book Review
Exploiting Histones Chromatin Structure and Gene Expression. Edited by Sarah C. R. Elgin. New York: IRL Press. (1995). 224 pp. $105.00, hardcover; $52.00, paperback.
Histones are emerging as substrates for activities controlling transcription. These structural proteins have recently been revealed as targets for post-translational modification (acetylation) by transcriptional adaptors (Brownell et al., Cell 84, 843–851, 1996). Some transcription repressors appear to reverse these modifications or interact directly with the unmodified histones (Hecht et al., Cell 80, 583–592, 1995; Taunton et al., Science 272, 408–410, 1996; Edmondson et al., Genes Dev., 10, 1247–1259, 1996). In addition, the nucleosome seems to structurally resemble TFIID; histones share dimerization motifs with several TATA-binding-protein associated factors, TAFs (Hoffman et al., Nature 380, 356–359). These dramatic discoveries are surely raising interest in histones and chromatin function. However, to understand the relevance of these results, one must appreciate the wealth of information and the unresolved questions regarding chromatin function. By revisiting the advances and conclusions derived in many of the premier systems and approaches used to analyze chromatin structure and function, this book will definitely bring new histone enthusiasts up to speed in this area. The approach taken by the editor strives to emphasize emerging concepts. Each chapter is co-authored by at least two scientists from different research groups. This works extremely well in some chapters, illustrating the similarities and differences in results from quite different experimental systems (for example, Chapter 5). In other chapters, which more closely resemble two distinct half chapters, this has served to provide a continuity of presentation. In addition, the authors have also read and provided comments on chapters other than their own. This has led to a “Discussion” section at the end of each chapter. This section and the preceding “Important Questions” section provides a stark realization of the unresolved issues. Thus this text provides the reader with a realistic mix of substantial advances and unanswered questions. Nucleosome and Chromatin Structure The first two chapters illustrate that a great deal is now known about the structure of the nucleosome core. The histone octamer is formed by the assembly of a series of histone dimers (Chapter 1). Two H3/H4 dimers form a stable tetramer which is then bound on either side by two H2A/H2B dimers. All four core histones share a common three helix structural motif termed the “histone fold” (also found in TFIID, Xie et al., Nature 380, 316–322, 1996), which clasps its dimerization partner over an extended interface. The structured part of the histone octamer interacts with DNA through a pattern of positive
charged amino acids which appear to follow the path of the DNA helix. These interactions and the preferred direction of DNA bending by specific sequences (Chapter 2) undoubtedly contribute to nucleosome positioning in some manner. Chapter 1 also makes it clear that beyond the internal structure of the nucleosome core, details of chromatin structure remain elusive. It describes the historical difficulties in determining higherorder chromatin structure and raises the possibility that the structure of the 30nM fiber is much more irregular than originally hoped.
Activating Chromatin: Remodeling Nucleosome Arrays The experimental systems described in the text provide three examples where transcription factors initiate the remodeling of pre-assembled nucleosome arrays (Chapters 4 and 5). Chapter 5 presents an informative comparison of nucleosome remodeling events which occur in vivo at the mouse mammary tumor virus promoter (MMTV) and the yeast PHO5 promoter upon gene induction. While the exact nature of the chromatin structural transitions remains under investigation it is clear that in both cases these changes are initiated by the binding of inducible transcription factors and occur in the absence of DNA replication. Similarly, the constitutive GAGA factor can initiate a structural transition (i.e. form a DNase 1 hypersensitive site) in pre-assembled nucleosome arrays at Drosophila heat-shock promoters in vitro (Chapter 4). Why then in the “Discussion” section of Chapter 4 do the authors raise the possibility that establishing transcriptional potential may involve DNA replication and chromatin reassembly (described in Chapter 3)? While not described in the text, experiments in synthetic nuclei have shown that a step including DNA replication can convert the transcriptional potential of the developmentally-regulated beta-globin promoter (Barton and Emerson, Genes Dev. 8, 2453–2465, 1994). Moreover, passing through S-phase appears important for establishing repressive heterochromatin structures. “At least one round of replication is required to restore repression to a conditionally de-repressed silent mating type locus” (Chapter 7, page 130). Thus, many important questions remain regarding the potential role of DNA replication in programming gene expression and its relationship to replication-independent mechanisms. Replication-independent transitions in chromatin structure are facilitated by ATP-dependent nucleosome disruption activities. These include the SWI/SNF complex (Chapter 5) and NURF, a distinct nucleosome-remodeling complex (Tsukiyama et al., Cell 83, 1021–1026, 1995). Chapters 4 and 6 illustrate that transcription regulation in chromatin may also occur during elongation. For example, the rate-limiting step in transcription from the Drosophila heat shock promoters is the release of a paused RNA polymerase by heat-shock factor (Chapter 4). RNA polymerase II elongation is inhibited by the presence of nucleosomes on template DNA resulting in increased pausing (Chapter 6). It is not known how
Cell 366
RNA polymerase II eventually transverses nucleosomes. However, a model system utilizing prokaryotic polymerases suggests a spooling mechanism of passing nucleosomes around an RNA polymerase (Chapter 6). Repressing Chromatin: Acting through Histones Chapters 7 and 8 suggest that stable repression is also an “active” process requiring the function of a distinct set of factors. Silencing in yeast and position effect variegation in Drosophila appear to result from the spreading of repressed “heterochromatic” structures. In yeast, silencing initiates at telomeres and silent mating type loci and is linked with both the function of specific repressing factors and the amino terminal regions of the core histones (Chapter 7). Indeed, recent reports illustrate a direct interaction between the Sir3p, Sir4p and Tup1p repressors and the unacetylated amino termini of H3 and H4 (Hecht et al., 1995; Edmondson et al., 1996). These results suggest that these factors interact directly with histone proteins to form a repressed chromatin structure counteracting the function of transcription activators and nucleosome disrupting activities like the SWI/SNF complex. This process is likely to be further modulated by histone acetylation which can reduce the interactions of the histones with the repressor proteins. In this light it is indeed exciting that the transcriptional adaptor protein, GCN5p, functions as a histone acetyltransferase (Brownell et al., 1996) and that the Rpd3p repressor may function as a histone deacetylase (Taunton et al., 1996). The text emphasizes similarities between silencing in yeast, heterochromatic spreading and homeotic silencing in Drosophila (Chapters 7 and 8). Both heterochromatic regions and homeotic silencing result in mitotically stable gene repression which can be mediated through proteins containing chromodomain motifs (i.e HP1 and the Pc-G proteins). It will be interesting to see whether any of these repressors interact directly or indirectly with histones. There are distinct differences in histone acetylation patterns in heterochromatic and euchromatic regions in Drosophila and in mammals. However, in mammals DNA methylation seems the strongest mediator of epigenetic decisions (Chapter 10). Important closely linked mammalian genes can be reciprocally imprinted (e.g. the Igf2 and H19; Chapter 10). Thus the mechanism of imprinting may be more complicated than the formation of open vs. condensed chromatin loops. Indeed, Chapter 9 discusses the challenges in correlating functional domains with the occurrence of DNA sequence elements that appear to bind the nuclear matrix. Functional elements are described that insulate from position effects and block enhancer function (LCRs and insulator elements). The effects of these elements in transgenic animals is striking, yet it remains unclear whether a functional domain represents a structural unit of chromatin.
Summary While not comprehensive, this text covers a substantial amount of important information in this field. The aspect of this book that distinguishes it from other texts on
this topic is that the approach taken by the editor has prevented dogmatic over interpretations. If the reader reaches the end of a chapter not quite understanding how it all fits together, reading the “Important Questions” and “Discussion” sections will likely indicate that neither do the authors. Thus, this text provides the most balanced and realistic view of the status of this field. Jerry L. Workman Department of Biochemistry and Molecular Biology and Center for Gene Regulation The Pennsylvania State University University Park, Pennsylvania 16802 Books Received Abelson, J.N. (1996). Methods in Enzymology Vol 267. Combinatorial Chemistry. Academic Press, San Diego, California. 493 pp. $85.00. Adolph, K.W. (1996). Human Molecular Genetics. Academic Press, Inc.. 500 pp. $85.00. Doolittle, R.F. (1996). Methods in Enzymology Vol 266. Computer Methods for Macromolecular Sequence Analysis. Academic Press, San Diego, California. 711 pp. $110.00. Eun, H.-M. (1996). Enzymology Primer for Recombinant DNA Technology. Academic Press, San Diego, California. 702 pp. $125.00. Fiskum, G. (1996). Neurodegenerative Diseases Molecular and Cellular Mechanisms and Therapeutic Advances. Plenum Publishing, New York. 482 pp. $135.00. Griffin, D.H. (1996). Fungal Physiology. Wiley Publishers, New York. 458 pp. $42.95. Kibbler, C., Mackenzie, D., and Odds, F. (1996). Principles and Practices of Clinical Mycology. Wiley Publishers, New York. 276 pp. $80.00. Paradise, L.J., Bendinelli, M., and Friedman, H. (1996). Enteric Infections and Immunity. Plenum Publishing, New York. 272 pp. $79.50. Rissler, J., Mellon, M. (1996). The Ecological Risks of Engineered Crops. The MIT Press, Cambridge, Massachusetts. 159 pp. $16.95. Smolensky, M.H., and Rensing, L. (1996). Chronobiology International The Journal of Biological and Medical Rhythm Research. Marcel Dekker, Monticello, New York. 80 pp. $175.00. Tomiuk, J., Wohrmann, K., and Sentker, A. (1996). Transgenic Organisms: Biological and Social Implications. Birkhauser, Basel, Switzerland. 263 pp. $83.95. Weinberg, R. A. (1996). Racing to the Beginning of the Road The Search for the Origin of Cancer. Harmony Books, New York, 1996. 270 pp. $27.50. Wirth, J. (1996). Color Atlas of Genetics. Thieme, New York. 411 pp. $29.00.