Long-range control of gene expression /

Front Cover 1
Long-Range Control of Gene Expression 4
Copyright Page 5
Contents 6
Contributors 12
Preface 14
Chapter 1: Chromatin Structure and the Regulation of Gene Expression: The Lessons of PEV in Drosophila 17
I. Introduction: Position Effect in Drosophila 18
II. Historical Background of the PEV Phenotype 21
A. The PEV phenotype and heterochromatin 22
B. Heterochromatin and euchromatin 23
III. Types of PEV 24
A. Chromosomal rearrangement PEV 24
B. Transposon insertion PEV 32
C. Pairing-dependent dominant PEV: Trans-inactivation 34
IV. Genome Organization and PEV 35
A. Chromatin structure 36
B. Nuclear organization 42
V. Concluding Remarks 45
Acknowledgments 47
References 47
Chapter 2: Polycomb Group Proteins and Long-Range Gene Regulation 61
I. Introduction 62
II. Genetic and Biochemical Characterization of PcG Proteins 64
III. PcG Mechanisms of Action 65
IV. PcG Proteins and Long-Range Gene Silencing 69
V. PcG and Very Long-Range Gene Silencing: \ 73
VI. Conclusions and Prospects 77
References 78
Chapter 3: Evolution of Cis-Regulatory Sequences in Drosophila 83
I. Introduction 84
A. Evolution of promoter sequences 85
B. Modularity 87
C. Experimental approaches to promoter evolution 87
II. Developmental Homeostasis, Sequence Turnover, and Stabilizing Selection 88
A. The P2 promoter of hunchback 89
B. The stripe 2 enhancer of even-skipped 91
C. The dorsocentral enhancer of scute 95
D. Conclusions 100
III. Enhancer Evolution and Loss or Gain of Traits 100
A. Evolution of yellow and variation in pigment patterns 101
B. Evolution of scute and variation in bristle patterns 103
C. Conclusions 106
IV. Cis-Trans Coevolution 107
A. The interaction between Bicoid and the hunchback P2 promoter 107
B. Conclusions 111
V. Evolution of New Regulatory Modules 111
VI. Conclusions 114
References 115
Chapter 4: beta-Globin Regulation and Long-Range Interactions 123
I. Introduction 124
II. The beta-Globin Locus 125
A. The beta-globin LCR 126
B. The chromatin structure of the beta-globin locus 128
C. Developmental regulation of beta-globin expression 129
III. Models of Long-Range Control of Gene Expression by Enhancers 131
A. The looping model 131
B. The tracking model 132
C. The linking model 132
D. Relocation models 133
IV. Long-Range Activation by the beta-Globin LCR 133
A. The LCR is in close proximity to the promoter 134
B. How are LCR-promoter contacts established? 137
C. How does the beta-globin LCR increase transcription efficiency? 140
V. Enhancement of Transcription by the beta-Globin LCR: Rate-Limiting Steps 143
A. Promoter remodeling 143
B. Transcription initiation 144
C. Promoter escape and elongation 146
VI. The Concept of an Active Chromatin Hub 147
VII. Future Directions 148
Acknowledgments 148
References 149
Chapter 5: Long-Range Regulation of alpha-Globin Gene Expression 159
I. Introduction 160
II. The Normal Structure and Evolution of the alpha-Globin Cluster 162
III. Functional Analysis of the alpha-Globin Regulatory Domain 163
IV. Structure of the Upstream Regulatory Elements and the Promoters 168
V. Transcription Factors Involved in Erythropoiesis 169
VI. Cellular Resources for Studying the Key Stages of Hematopoiesis 173
VII. Transcription Factor Binding to the Upstream Regulatory Elements 174
VIII. Transcription Factor Binding to the Promoter 175
IX. The Recruitment of RNA Polymerase and GTFs to the alpha-Globin Cluster 176
X. What Role Do the Remote Regulatory Elements Play? 177
XI. How Do the Upstream Elements Interact with the Promoter? 178
XII. Sequential Activation of the alpha-Globin Gene Cluster During Differentiation 181
XIII. Conclusions, Speculation, and Future Directions 182
Acknowledgments 185
References 185
Chapter 6: Global Control Regions and Regulatory Landscapes in Vertebrate Development and Evolution 191
I. Introduction 192
II. Global Controls 194
A. Clusters of co-expressed developmental genes 194
B. Shared regulatory elements between neighboring genes 197
C. Global regulation in Hox cluster 199
III. Co-Expression Chromosomal Territories, Regulatory Landscapes, and Global Control Regions 201
A. Extending away from the Hox cluster: Evx2 and Lnp 201
B. Gremlin/Formin 202
C. Co-expression territories 203
IV. Mechanisms of Underlying Global Regulation 204
V. Co-Expression Chromosomal Territories, Regulatory Landscapes: Bystander Effects or Functional Operons? 208
VI. Evolutionary Implications of Global Gene Control 211
VII. Global Regulation, Chromosomal Architecture, and Genetic Disorders 213
VIII. Concluding Remarks 213
References 214
Chapter 7: Regulation of Imprinting in Clusters: Noncoding RNAs Versus Insulators 223
I. Introduction 224
II. Insulator Model of Regulation 225
A. The H19/Igf2 imprinted cluster 225
B. Evidence for insulator-mediating silencing at the Rasgrf1 locus 227
III. The ncRNA Model of Regulation 228
A. The Air and Igf2r cluster 228
B. ncRNA and the Kcnq1 locus 230
IV. Dlk1/Gtl2 Imprinted Cluster: A Bit of Everything 231
V. Conclusions 234
Acknowledgments 235
References 235
Chapter 8: Genomic Imprinting and Imprinting Defects in Humans 241
I. Introduction 242
II. The Mechanisms of Genomic Imprinting 242
A. The nature of genomic imprints 242
B. Erasure, establishment, and maintenance of genomic imprints 245
III. Imprinting Defects 246
A. Imprinting defects in 15q11-q13 246
B. Imprinting defects in 11p15 255
IV. Conclusions 258
References 259
Chapter 9: Epigenetic Gene Regulation in Cancer 263
I. Introduction 264
II. Cancer Cells Show A Disruption of DNA Methylation Patterns 266
III. Disruption of the Histone Modification Profile in Cancer 269
IV. Cascades of Epigenetic Deregulation in Cancer 272
V. What Are the Mechanisms That Lead to Aberrant Methylation Patterns in Cancer? 274
VI. Epigenetic Therapy for Cancer Treatment 277
Acknowledgments 278
References 278
Chapter 10: Genomic Identification of Regulatory Elements by Evolutionary Sequence Comparison and Functional Analysis 285
I. Introduction 286
II. Genomic Architecture of the Human Genome 287
A. Distant regulatory elements controlling transcription 289
B. Noncoding mutations causing human disease 290
III. Computational Methods of Predicting Regulatory Elements 292
A. Identifying evolutionarily conserved noncoding sequences 292
B. Predicting TFBSs 296
IV. In Vivo Validation and Characterization of Transcriptional Regulatory Elements 298
A. Enhancer validation using transient transgenesis 298
B. Identifying distant enhancers using large genomic constructs 300
C. Mutating candidate regulatory elements in engineered mice 301
V. Conclusions 302
References 303
Chapter 11: Regulatory Variation and Evolution: Implications for Disease 311
I. Introduction 312
II. Evolution and Variation of Noncoding DNA 313
III. Natural Selection in Noncoding DNA 316
IV. Gene Expression Studies 317
V. Disease Implications 318
VI. Conclusions 319
References 320
Chapter 12: Organization of Conserved Elements Near Key Developmental Regulators in Vertebrate Genomes 323
I. Introduction 324
II. Gene-Regulatory Networks in Development 325
III. Identification of Evolutionarily Constrained Sequences Using Phylogenetic Footprinting 326
IV. Searches for Regulatory Elements Using EvolutionaryConservation 326
V. Takifugu Rubripes: A Compact Model Genome 328
VI. Identification of Enhancer Elements Through Fish-Mammal Comparisons 329
VII. Fish-Mammal Conserved Noncoding Elements Are Associated with Vertebrate Development 331
VIII. High-Resolution Analysis of the Organization of CNEs Around Key Developmental Regulators 333
IX. General Genomic Environment Around CNEs 333
X. CNEs Present in Transcripts 335
XI. CNEs Located Within UTRs 337
XII. CNEs Are Located Large Distances Away from Their Putative Target Gene 339
A. Mutation events in and around CNEs over evolution 340
XIII. Discussion 344
References 349
Chapter 13: Long-Range Gene Control and Genetic Disease 355
I. From Genetic Disease to Long-Range Gene Regulation 356
II. Position Effect Revisited 358
A. Thalassemias and the alpha- and beta-globin loci 358
III. Loss of a Positive Regulator 361
A. Van Buchem disease 361
B. Leri-Weill dyschondrosteosis 362
IV. TWIST, POU3F4, PITX2, SOX3, GLI3, and FOXP2 362
V. The \ 369
A. Aniridia and PAX6 369
VI. MAF, SDC2, TGFB2, REEP3, and PLP1 371
VII. Two Position Effects\u2014Different Outcomes 373
A. Sonic hedgehog, holoprosencephaly, and preaxial polydactyly 373
VIII. Phenotypes Resulting from Position Effects on More than One Gene 378
A. Split hand foot malformation locus 1 378
B. Combination of two position effects in SHH and RUNX2 379
IX. Global Control Regions; HOXD, Gremlin, and Limb Malformations 379
X. FOX Genes and Position Effects 381
A. FOX genes in eye anomalies 381
XI. SOX9 and Campomelic Displasia 382
XII. Facioscapulohumeral Dystrophy 384
XIII. Aberrant Creation of an Illegitimate siRNA Target Site 386
XIV. Genetic Disease Due to Aberrant Gene Transcription Can Be Caused by Many Different Mechanisms 387
A. The problem: How to find and assess regulatory mutations? 388
B. Long-range control and genome organization 390
C. Implications for (common) genetic disease 393
XV. Concluding Remarks 394
References 395
Index 405