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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