Modifications of Nuclear DNA and its Regulatory Proteins (eBook)

Front Cover 1
Modifications of Nuclear DNA and its Regulatory Proteins 4
Copyright 5
Contents 6
Contributors 12
Preface 14
Chapter 1: Introduction-Epiphanies in Epigenetics 16
I. What is an Epigenetic Code? 17
II. Inheritance 21
III. Modularity of Epigenetic Modifiers 22
Acknowledgments 29
References 29
Section I: Evolution of DNA Methylation 38
Chapter 2: Natural History of Eukaryotic DNA Methylation Systems 40
I. Introduction 42
II. DNA Methyltransferases 45
III. 5mC Demethylation and Potential DNA Demethylases 68
IV. Further Modifications of 5mC in Eukaryotic DNA 78
V. Domains Involved in Discrimination of Methylated Versus Nonmethylated Cytosines in DNA 84
VI. Domain Architectural Logic of Proteins Related to DNA Methylation 96
VII. Evolutionary Considerations 100
VIII. General Conclusions 103
Acknowledgments 105
Appendix Supplementary Material 105
Note Added in Proof 105
References 105
Chapter 3: Natural History of the Eukaryotic Chromatin Protein Methylation System 120
I. Introduction 122
II. The Categories of Protein Methylases and Their Role in Chromatin Protein Methylation 126
III. Enzymatic Mechanisms That Preempt or Reverse the Action of Protein Methylases in Chromatin 148
IV. Domains Involved in Discrimination of Methylated Peptides 162
V. Domain Architectures of Enzymes in the Chromatin Protein Methylation Network 169
VI. Evolutionary Considerations 174
VII. General Conclusions 177
Acknowledgments 178
Supplementary Information 178
References 178
Chapter 4: DNA Methylation in Drosophila-A Critical Evaluation 192
I. Evidence for 5-Methyl Cytosine in Drosophila 193
II. Evidence for DNA Methylation Activity of Dnmt2 Enzymes 195
III. Methylation of tRNA by Dnmt2 197
IV. Biological Function of Dnmt2 in Drosophila 199
V. Dinucleotide Abundances in "Dnmt2-only" Organisms: A Hint of DNA Methylation? 200
VI. Methyl-Binding Proteins in Drosophila-Evidence, Concepts, and Inconsistencies 202
Acknowledgment 203
References 203
Chapter 5: DNA Methylation in Zebrafish 208
I. Introduction 209
II. Methylation Profile of the Zebrafish Genome 210
III. The Zebrafish Methylation Machinery 212
IV. Link Between DNA and Histone Modification in Zebrafish 222
V. DNA Methylation Dynamics in Early Development 223
VI. Evidence for Active DNA Demethylation in Zebrafish 224
VII. Perspectives and Future Directions 226
VIII. Conclusions 228
References 229
Section II: Mammalian DNA Methyltransferases - Structure and Function 234
Chapter 6: Dnmt1: Structure and Function 236
I. Introduction 237
II. The Functional Domains of Dnmt1 and Dnmt1 Inhibitors 239
III. Structure and Function of Dnmt1 and Its Interaction with Other Molecules 251
IV. New Crystal Structures of Large C-Terminal Fragment of Mouse and Human Dnmt1 258
References 260
Chapter 7: The DNMT3 Family of Mammalian De Novo DNA Methyltransferases 270
I. Introduction 271
II. Discovery, Primary Structure, and Expression of Mammalian DNMT3A and DNMT3B 272
III. DNMT3A and DNMT3B Drive the Establishment of DNA Methylation Patterns De Novo 274
IV. The DNMT3L Protein, an Essential Accessory Factor for De Novo Methylation 284
V. Interactions Between the De Novo DNA Methylation Machinery and Chromatin 289
VI. Concluding Remarks and Outstanding Questions 292
Acknowledgments 292
References 292
Section III: DNA Methylation and Demethylation 302
Chapter 8 Recruitment of Dnmt1: Roles ofthe SRA Protein Np95 (Uhrf1)and Other Factors 304
I. Roles for DNA Methylation in Transcriptional Regulation and Development 305
II. Maintenance and De Novo DNA Methyltransferases: Two Modes of Action 306
III. Localization of Dnmt1 into Hemimethylated DNA: Search for Recruiter Molecule(s) 307
IV. Np95 Is a Cell Cycle-Associated Protein That Localizes to the RF During S-Phase 308
V. Np95 Protein Domains: SRA and More 309
VI. Np95 Recruits Dnmt1 into Hemimethylated Sites During DNA Replication 311
VII. Np95 Is Required for Global DNA Methylation 313
VIII. Other Factors That Recruit/Interact with Dnmt1 314
IX. Concluding Remarks and Future Directions 320
References 322
Chapter 9: Regulation of Expression and Activity of DNA (Cytosine-5) Methyltransferases in Mammalian Cells 326
I. Transcriptional and Posttranscriptional Regulation of DNMTs 327
II. Regulation of DNMTs by Posttranslational Modifications 332
III. Altered Regulation of DNMTs During Disease 335
IV. Drug-Induced Reductions in DNMT Levels 341
V. Concluding Remarks and Future Directions 343
Acknowledgments 344
References 344
Chapter 10: Mechanistic and Functional Links Between Histone Methylation and DNA Methylation 350
I. Introduction 350
II. An Evolutionarily Conserved Pathway Between H3K9 Methylation and DNA Methylation 352
III. A Role for LSD1 in Coordinating Histone and DNA Methylation? 354
IV. H3K4 Demethylation and Genomic Imprinting 356
V. Concluding Remarks 358
References 359
Section IV: DNA Methylation and Silencing 364
Chapter 11: RNA-Mediated Silencing Mechanisms in Mammalian Cells 366
I. Introduction 367
II. RNA Constitutes a Structural Component of the Mammalian Cell Nucleus 367
III. A Role for RNAs in Regulating Chromatin Modifications and Organization 368
IV. Repression of Ribosomal DNA Repeats by the NoRC Repressor Complex Is Regulated by IGS Noncoding RNAs 379
V. Pervasive Transcription: RNA at Centromeric and Telomeric Chromatin 381
VI. Aspects of the Evolution of Regulatory RNAs 382
VII. Concluding Remarks and Future Directions in RNA Research 384
Acknowledgment 384
References 385
Chapter 12: Biological Functions of Methyl-CpG-Binding Proteins 392
I. Introduction 393
II. Families of Methyl-CpG-Binding Proteins 394
III. Biological Functions of Methyl-CpG-Binding Proteins 401
IV. Methyl-CpG-Binding Proteins and Human Disease 404
V. Concluding Remarks 406
Acknowledgments 407
References 407
Section V: DNA Methylation in Medicine 414
Chapter 13: Diseases Associated with Genomic Imprinting 416
I. Overview of Genomic Imprinting 417
II. Disorders Associated with Particular Imprinted Genes and Regions 421
III. Psychiatric Disorders and Other Behavioral Effects 437
IV. The Cost of Imprinting 441
V. Conclusions 446
References 446
Chapter 14: DNA Methylation Changes in Cancer 462
I. Introduction 462
II. Mechanism Underlying DNA Methylation Changes in Cancer 463
III. The Roles of DNA Methylation in Cancer Signaling Pathways 464
IV. Genetic and Epigenetic Interaction in Cancer 466
V. Hypomethylation in Cancer 466
VI. Epigenetic Therapy 468
VII. Conclusions and Future Directions 469
Acknowledgments 469
References 469
Chapter 15: Genome-Wide Distribution of DNA Methylation at Single-Nucleotide Resolution 474
I. Impact of Single-Nucleotide-Based Detection on DNA Methylome Profiling 475
II. Overview of Molecular Approaches Used for Methylation Studies 476
III. DNA Methylation Patterns at Single-Nucleotide Resolution 485
IV. DNA Methylation, Histone Modifications, and Other Epigenetic Regulation 487
V. Detection of the 6th Base (5-Hydroxymethylcytosine) and Future Perspectives 488
VI. Concluding Remarks 488
References 489
Index 494
Colour Plate 504