Gene regulation : a eukaryotic perspective

Preface to the fifth edition xii Preface to the first edition xiii Preface to the second edition xiv Preface to the third edition xv Preface to the fourth edition xvi Acknowledgments xvii 1 Tissue-specific expression of proteins and messenger RNAs 1 Summary 1 1.1 Introduction 1 1.2 Tissue-specific expression of proteins 1 Specific methods for studying the protein composition of tissues 2 General methods for studying the protein composition of tissues 4 1.3 Tissue-specific expression of messenger RNAs 7 Specific methods for studying the mRNAs expressed in 7 different tissues General methods for studying the mRNAs expressed in 9 different tissues 1.4 Conclusions 13 References 13 2 The DNA of different cell types is similar in both amount and type 15 Summary 15 2.1 Introduction 15 2.2 DNA loss 15 DNA loss as a mechanism of gene regulation 15 Chromosomal studies 16 Functional studies 20 Molecular studies 23 2.3 DNA amplification 24 DNA amplification as a mechanism of gene regulation 24 Chromosomal studies 25 Molecular studies 27 2.4 DNA rearrangement 29 2.5 Conclusions 35 References 36 3 Gene expression 39 Summary 39 3.1 Levels of gene regulation 39 3.2 Transcription 41 RNA polymerase I 41 RNA polymerase III 43 RNA polymerase II 47 Common features of transcription by the three different RNA polymerases 51 3.3 Post transcriptional events 54 Capping 55 Polyadenylation 57 RNA splicing 59 Coupling of transcription and RNA processing within the nucleus 64 RNA transport 66 Translation 70 3.4 Conclusions 74 References 75 4 Regulation at transcription 79 Summary 79 4.1 Introduction 79 4.2 Evidence for transcriptional regulation 79 Evidence from studies of nuclear RNA 79 Evidence from pulse-labeling studies 84 Evidence from nuclear run-on assays 85 Evidence from polytene chromosomes 88 4.3 Regulation at transcriptional elongation 91 Initiation of transcription 91 Transcriptional elongation 92 4.4 Conclusions 96 References 96 5 Post-transcriptional regulation 99 Summary 99 5.1 Regulation after transcription? 99 5.2 Regulation of RNA splicing 100 RNA splicing 100 Alternative RNA splicing 100 Mechanism of alternative RNA splicing 109 Generality of alternative RNA splicing 115 5.3 RNA editing 116 5.4 Regulation of RNA transport 118 Transport from nucleus to cytoplasm 118 Transport within the cytoplasm 121 5.5 Regulation of RNA stability 123 Cases of regulation by alterations in RNA stability 123 Mechanisms of stability regulation 125 Role of stability changes in regulation of gene expression 127 5.6 Regulation of translation 129 Cases of translational control 129 Mechanism of translational control 129 Significance of translational control 139 5.7 Inhibition of gene expression by small RNAs 139 5.8 Conclusions 141 References 142 6 Transcriptional control – chromatin structure 147 Summary 147 6.1 Introduction 147 6.2 Commitment to the differentiated state and its stability 150 6.3 Chromatin structure 153 6.4 Changes in chromatin structure in active or potentially active genes 157 Active DNA is organized in a nucleosomal structure 157 Sensitivity of active chromatin to DNaseI digestion 158 6.5 Alterations in DNA methylation in active or potentially active genes 162 Nature of DNA methylation 162 Evidence that DNA methylation plays a role in regulating 164 chromatin structure Mechanism by which DNA methylation affects chromatin structure 166 6.6 Modification of histones in the chromatin of active or potentially 168 active genes Acetylation 169 Ubiquitination and sumoylation 172 Phosphorylation 173 Methylation 175 6.7 Changes in chromatin structure in the regulatory regions of active 178 or potentially active genes DNaseI hypersensitive sites 178 Chromatin remodeling by proteins capable of displacing 184 nucleosomes or altering their structure 6.8 Other situations in which chromatin structure is regulated 189 X-chromosome inactivation 190 Genomic imprinting 192 6.9 Conclusions 196 References 197 7 Transcriptional control – DNA sequence elements 203 Summary 203 7.1 Introduction 203 Relationship of gene regulation in prokaryotes and eukaryotes 203 Coordinately regulated genes are not linked in eukaryotes 203 The Britten and Davidson model for the coordinate regulation 205 of unlinked genes 7.2 Short sequence elements located within or adjacent to the gene promoter 206 Short regulatory elements 206 The 70 kDa heat-shock protein gene 207 Other response elements 211 DNA binding by short sequence elements 213 Mechanism of action of promoter regulatory elements 219 7.3 Enhancers 220 Regulatory sequences that act at a distance 220 Tissue-specific activity of enhancers 221 Mechanism of action of enhancers 224 7.4 Negatively acting sequence elements 229 Silencers 229 Insulators 231 7.5 Locus control regions 232 The locus control region 232 Mechanism of action of LCRs 234 7.6 Regulation of transcription by RNA polymerases I and III 236 7.7 Conclusions 239 References 240 8 Transcriptional control – transcription factors 243 Summary 243 8.1 Introduction 243 8.2 DNA binding by transcription factors 247 Introduction 247 The helix-turn-helix motif 247 The zinc finger motif 256 The leucine zipper, the helix-loop-helix motif and the basic 264 DNA binding domain Other DNA binding domains 267 8.3 Regulation of transcription 268 Introduction 268 Activation domains 269 How is transcription activated? 272 Repression of transcription 282 8.4 What regulates the regulators? 286 Introduction 286 Regulated synthesis of transcription factors 287 Regulated activity of transcription factors 289 8.5 Conclusions 299 References 301 9 Gene regulation and human disease 307 Summary 307 9.1 Gene regulation and human disease 307 Transcriptional regulators 308 Chromatin remodeling factors 312 Post-transcriptional events 314 9.2 Proto-oncogenes 315 9.3 Elevated expression of oncogenes 319 9.4 Transcription factors as oncogenes 324 Fos, Jun and AP1 325 v-erbA and the thyroid hormone receptor 327 Other transcription factor-related oncogenes 331 9.5 Anti-oncogenes 334 Nature of anti-oncogenes 334 p53 335 The retinoblastoma protein 339 Other anti-oncogene transcription factors 342 9.6 Oncogenes/anti-oncogenes: the relationship of cancer and 343 normal cellular function 9.7. Gene regulation and therapy of human diseases 345 9.8. Conclusions 351 References 352 10 Conclusions and future prospects 357 Index 363