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Introduction1

CHAPTER 1·Lessons from Bacteria11

RNA POLYMERASE11

REGULATED RECRUITMENT:THE Iac GENES13

Protein-DNA Interactions15

Detecting Physiological Signals16

Promoter Recognition and Transcription by RNA Polymerase17

Switching the Genes On:Activation by CAP18

Cooperative Binding of Proteins to DNA18

Cooperative Binding and Gene Activation by CAP21

Repression by Lac Repressor25

Interim Summary and Extension25

MORE REGULATED RECRUITMENT:THE BACTERIOPHAGE λ26

The Switch28

Establishing Lysogeny29

Analogies with lac31

Promoters32

Protein-DNA Interactions32

Repression32

Activation32

Detecting Physiological Signals33

Making an Efficient Switch34

Cooperative Binding of λ Repressor to DNA34

Autogenous Control by Repressor37

PANEL:Antitermination:N and Q38

Interim Summary and Extensions39

Activation:A Closer Look39

DNA binding:A Closer Look41

Synergy41

POLYMERASE ACTIVATION:glnA AND RELATED GENES42

Detecting the Physiological Signal43

Activation by NtrC43

DNA Binding by NtrC43

Promoter Recognition by σ54-containing Polymerase43

Other Activators of σ54 Polymerase45

Interim Summary45

PANEL:Phage T4 Late Genes47

PROMOTER ACTIVATION:merT AND RELATED GENES47

Promoter Recognition47

Detecting the Physiological Signal and Activation48

Interim Summary48

GENERAL SUMMARY49

PANEL:More on Repression in Bacteria51

FOOTNOTES53

BIBLIOGRAPHY55

CHAPTER 2·Yeast:A Single-celled Eukaryote59

RNA POLYMERASE60

OTHER PARTS OF THE TRANSCRIPTIONAL MACHINERY60

A MODEL CASE:THE GAL GENES63

AN OVERVIEW OF ACTIVATION63

Overview of Regulation of a GAL Gene64

Specific DNA Binding65

Detecting Physiological Signals66

HOW Gal4 WORKS67

Separate DNA-binding and Activating Regions of Gal467

Activating Region Structure71

Independent Mutations Can Increase Activator Strength Additively When Combined72

Activating Regions Work with an Efficiency Proportional to Their Lengths72

New Activating Regions Are Easily Generated73

Activating Region-Target Interactions Tolerate Sequence Changes73

Squelching75

Recruitment Visualized76

Activator Bypass Experiments76

Activation by a Heterologous Protein-Protein Interaction78

Direct Tethering of the Transcriptional Machinery80

PANEL:Activator Bypass Experiments81

How does Gal4 Recruit Polymerase?82

Nucleosomes and Their Modifiers83

Targets of Gal4:Experiments Performed In Vitro84

Action of Gal4:Experiments Performed In Vivo85

What Is Required for Activation?86

What Appears at the Gene Upon Activation?86

Imposing a Need for Nucleosome Modifiers87

Weakening the Gal4-binding Sites or the Gal4-activating region87

Cell-cycle Stage-dependent Requirement for Nucleosome Modifiers89

Activation:An Interim Summary89

Repression by Migl91

SIGNAL INTEGRATION AND COMBINATORIAL CONTROL92

Cooperative Binding with Alternative Partners93

Sequential Binding of Activators94

SILENCING95

Heterochromatic Chromosomal Regions95

Compartmentalization98

PANEL:Variegation Visualized99

PANEL:Epigenetics100

DNA LOOPING101

SUMMARY103

FOOTNOTES104

BIBLIOGRAPHY110

CHAPTER 3·Some Notes on Higher Eukaryotes115

MECHANISM OF ACTIVATION:RECRUITMENT116

WHAT IS RECRUITED?118

Transcriptional Machinery and Promoters118

Targets119

Nucleosomal Templates119

The Human Interferon-β Gene121

The Drosophila HSP70 Gene122

REPRESSION122

DETECTING AND TRANSMITTING PHYSIOLOGICAL SIGNALS123

Transport Into and Out of the Nucleus123

Phosphorylation of Inhibitor or Activator in the Nucleus124

PANEL:Transport-dependent Proteolysis:The Case of SREBP125

The Human Interferon-β Enhancer126

Allosteric Change of DNA-bound Activator126

SIGNAL INTEGRATION,COMBINATORIAL CONTROL,AND ALTERNA-TIVE ENHANCERS126

The Drosophila eve Gene128

ACTION AT A DISTANCE129

DNA METHYLATION,INSULATORS,AND IMPRINTING132

CHROMOSOMAL POSITION AND GENE EXPRESSION134

COMPARTMENTALIZATION135

OVERVIEW136

FOOTNOTES137

BIBLIOGRAPHY140

CHAPTER 4·Enzyme Specificity and Regulation143

UBIQUITYLATION AND PROTEOLYSIS144

SPLICING146

IMPOSING SPECIFICITY ON KINASES148

Cyclin-dependent Kinases149

Transcriptional Antitermination by TAT150

Cytokine Receptors and Signaling through STATs152

Growth Factor Receptors154

INTERIM SUMMARY AND EXTENSIONS156

Kinases157

Phosphatases158

Interpreting Signals159

FURTHER GENERALIZATIONS160

Dangers160

Interpreting Experiments162

Benefits163

FOOTNOTES167

BIBLIOGRAPHY170

Afterword173

Appendices177

Appendix 1:More on Cooperativity177

Appendix 2:Topogenic Sequences183

Appendix 3:All-or-none Effects and Levels of Gene Expression185

Index187