Introduction 1
CHAPTER 1·Lessons from Bacteria 11
RNA POLYMERASE 11
REGULATED RECRUITMENT:THE Iac GENES 13
Protein-DNA Interactions 15
Detecting Physiological Signals 16
Promoter Recognition and Transcription by RNA Polymerase 17
Switching the Genes On:Activation by CAP 18
Cooperative Binding of Proteins to DNA 18
Cooperative Binding and Gene Activation by CAP 21
Repression by Lac Repressor 25
Interim Summary and Extension 25
MORE REGULATED RECRUITMENT:THE BACTERIOPHAGE λ 26
The Switch 28
Establishing Lysogeny 29
Analogies with lac 31
Promoters 32
Protein-DNA Interactions 32
Repression 32
Activation 32
Detecting Physiological Signals 33
Making an Efficient Switch 34
Cooperative Binding of λ Repressor to DNA 34
Autogenous Control by Repressor 37
PANEL:Antitermination:N and Q 38
Interim Summary and Extensions 39
Activation:A Closer Look 39
DNA binding:A Closer Look 41
Synergy 41
POLYMERASE ACTIVATION:glnA AND RELATED GENES 42
Detecting the Physiological Signal 43
Activation by NtrC 43
DNA Binding by NtrC 43
Promoter Recognition by σ54-containing Polymerase 43
Other Activators of σ54 Polymerase 45
Interim Summary 45
PANEL:Phage T4 Late Genes 47
PROMOTER ACTIVATION:merT AND RELATED GENES 47
Promoter Recognition 47
Detecting the Physiological Signal and Activation 48
Interim Summary 48
GENERAL SUMMARY 49
PANEL:More on Repression in Bacteria 51
FOOTNOTES 53
BIBLIOGRAPHY 55
CHAPTER 2·Yeast:A Single-celled Eukaryote 59
RNA POLYMERASE 60
OTHER PARTS OF THE TRANSCRIPTIONAL MACHINERY 60
A MODEL CASE:THE GAL GENES 63
AN OVERVIEW OF ACTIVATION 63
Overview of Regulation of a GAL Gene 64
Specific DNA Binding 65
Detecting Physiological Signals 66
HOW Gal4 WORKS 67
Separate DNA-binding and Activating Regions of Gal4 67
Activating Region Structure 71
Independent Mutations Can Increase Activator Strength Additively When Combined 72
Activating Regions Work with an Efficiency Proportional to Their Lengths 72
New Activating Regions Are Easily Generated 73
Activating Region-Target Interactions Tolerate Sequence Changes 73
Squelching 75
Recruitment Visualized 76
Activator Bypass Experiments 76
Activation by a Heterologous Protein-Protein Interaction 78
Direct Tethering of the Transcriptional Machinery 80
PANEL:Activator Bypass Experiments 81
How does Gal4 Recruit Polymerase? 82
Nucleosomes and Their Modifiers 83
Targets of Gal4:Experiments Performed In Vitro 84
Action of Gal4:Experiments Performed In Vivo 85
What Is Required for Activation? 86
What Appears at the Gene Upon Activation? 86
Imposing a Need for Nucleosome Modifiers 87
Weakening the Gal4-binding Sites or the Gal4-activating region 87
Cell-cycle Stage-dependent Requirement for Nucleosome Modifiers 89
Activation:An Interim Summary 89
Repression by Migl 91
SIGNAL INTEGRATION AND COMBINATORIAL CONTROL 92
Cooperative Binding with Alternative Partners 93
Sequential Binding of Activators 94
SILENCING 95
Heterochromatic Chromosomal Regions 95
Compartmentalization 98
PANEL:Variegation Visualized 99
PANEL:Epigenetics 100
DNA LOOPING 101
SUMMARY 103
FOOTNOTES 104
BIBLIOGRAPHY 110
CHAPTER 3·Some Notes on Higher Eukaryotes 115
MECHANISM OF ACTIVATION:RECRUITMENT 116
WHAT IS RECRUITED? 118
Transcriptional Machinery and Promoters 118
Targets 119
Nucleosomal Templates 119
The Human Interferon-β Gene 121
The Drosophila HSP70 Gene 122
REPRESSION 122
DETECTING AND TRANSMITTING PHYSIOLOGICAL SIGNALS 123
Transport Into and Out of the Nucleus 123
Phosphorylation of Inhibitor or Activator in the Nucleus 124
PANEL:Transport-dependent Proteolysis:The Case of SREBP 125
The Human Interferon-β Enhancer 126
Allosteric Change of DNA-bound Activator 126
SIGNAL INTEGRATION,COMBINATORIAL CONTROL,AND ALTERNA-TIVE ENHANCERS 126
The Drosophila eve Gene 128
ACTION AT A DISTANCE 129
DNA METHYLATION,INSULATORS,AND IMPRINTING 132
CHROMOSOMAL POSITION AND GENE EXPRESSION 134
COMPARTMENTALIZATION 135
OVERVIEW 136
FOOTNOTES 137
BIBLIOGRAPHY 140
CHAPTER 4·Enzyme Specificity and Regulation 143
UBIQUITYLATION AND PROTEOLYSIS 144
SPLICING 146
IMPOSING SPECIFICITY ON KINASES 148
Cyclin-dependent Kinases 149
Transcriptional Antitermination by TAT 150
Cytokine Receptors and Signaling through STATs 152
Growth Factor Receptors 154
INTERIM SUMMARY AND EXTENSIONS 156
Kinases 157
Phosphatases 158
Interpreting Signals 159
FURTHER GENERALIZATIONS 160
Dangers 160
Interpreting Experiments 162
Benefits 163
FOOTNOTES 167
BIBLIOGRAPHY 170
Afterword 173
Appendices 177
Appendix 1:More on Cooperativity 177
Appendix 2:Topogenic Sequences 183
Appendix 3:All-or-none Effects and Levels of Gene Expression 185
Index 187