Handbook of Epigenetics: The New Molecular and Medical Genetics

Description

Epigenetics is considered by many to be the "new genetics" because the realization that many biological phenomena are controlled not through gene mutations, but rather through reversible and heritable epigenetic processes that have opened up new paths for discovery. The biological processes impacted by epigenetics range from tissue/organ regeneration, X-chromosome inactivation, and stem cell differentiation to genomic imprinting and aging. The effects of epigenetics are vast and encompass lower organisms as well as humans. Aberrations of epigenetics influence many diseases involving but not limited to cancer, immune disorders, neurological and metabolic disorders, and imprinting diseases. Clinical intervention is already in place for some of these disorders and many novel epigenetic therapies are on the horizon. This comprehensive collection of reviews written by leaders in the field of epigenetics provides a broad view of this important and evolving topic. From molecular mechanisms and epigenetic technology to discoveries in human disease and clinical epigenetics the nature and applications of the science will be presented for those with interests ranging from the fundamental basis of epigenetics to therapeutic interventions for epigenetic-based disorders. *  Contributions by leading international investigators involved in molecular research and clinical and therapeutic applications *  Integrates methods and biological topics with basic and clinical discoveries *  Includes coverage of new topics in epigenetics such as prions, regulation of long-term memory by epigenetics, metabolic aspects of epigenetics, and epigenetics of neuronal disorders Cover Page\r......Page 1 Front matter......Page 2 Copyright......Page 4 Contributors......Page 5 Preface......Page 10 The basics of DNA methylation and histone modifications......Page 11 Epigenetic technology......Page 12 Metabolism and epigenetics......Page 13 Epigenetic epidemiology......Page 14 Conclusion......Page 15 References......Page 16 Introduction......Page 17 Dnmt3L is a regulatory factor for de novo DNA methylation......Page 18 Dimeric Dnmt3a suggests de novo DNA methylation depends on CpG spacing......Page 19 A structural fragment of Dnmt1......Page 21 Base flipping mechanism......Page 22 UHRF1-histone interactions......Page 23 Replication-coupled crosstalk between DNA methylation and histone modifications......Page 24 DNA demethylation via hydroxylation?......Page 25 Conclusion and perspectives......Page 26 References......Page 27 Histone modifications......Page 36 Ubiquitination......Page 38 ADP-ribosylation......Page 39 Role of histone phosphorylation in transcription regulation......Page 40 Role of histone phosphorylation in DNA repair......Page 41 Role of histone methylation in transcription regulation......Page 42 First Classification......Page 44 p300/CBP......Page 45 HAT complexes......Page 46 Role of histone acetylation in transcription regulation......Page 47 Role of histone acetylation in DNA repair......Page 48 References......Page 49 Introduction......Page 57 Short ncRNAs and epigenetics......Page 58 Long ncRNAs and epigenetics......Page 62 Conclusions......Page 65 Acknowledgements......Page 66 References......Page 67 Prions and Prion-like Phenomena in Epigenetic Inheritance......Page 70 Prions of S. cerevisiae and P. anserina......Page 71 Cytotaxis of Cilia and Other Complex Structures......Page 74 Mixed heredity: A prion that propagates by covalent auto-activation......Page 75 The Lactose Operon and its Positive Feedback Loop......Page 76 Crippled Growth, a Self-Sustained and Mitotically Inheritable Signaling Pathway in the Filamentous Fungus Podospora anserina......Page 77 Conclusion......Page 78 References......Page 79 Introduction......Page 85 CPE and TPE, lessons from model organisms......Page 86 Setting the frontiers of chromatin domains......Page 89 Chromosomal position effect in human pathologies......Page 93 Split-Hand/Foot Malformation Type 1: Position Effect Involving Several Genes?......Page 94 PLP1 and Pelizaeus–Merzbacher Disease: When Position Effect Rescues the Phenotype......Page 96 Alpha-Thalassemia......Page 97 Disorders of unstable repeat expansions......Page 98 Copy number variants: a new challenge in the deciphering of CPE......Page 99 Telomeric position effect in human pathologies......Page 100 Position effects and aging......Page 101 Conclusions......Page 102 References......Page 103 PRC1......Page 116 PRC2......Page 117 Recruiters......Page 118 The H3K27 methyl mark......Page 119 Recruitment by H3K27me3 ......Page 120 Epigenetic maintenance or cellular memory......Page 121 Maintenance of the non-repressed state......Page 122 The bivalent state......Page 123 Differentiation......Page 124 References......Page 125 Principles of DNA methylation analysis......Page 131 Bisulfite Sequencing......Page 133 Real-time MSP and MethyLight......Page 135 PCR Conditions for Unbiased Amplification......Page 136 PCR Conditions for Specific Amplification......Page 137 References......Page 139 Introduction......Page 141 Restriction landmark genomic scanning (RLGS)......Page 142 Techniques based on methylation-sensitive restriction endonucleases and PCR......Page 143 Methylation-specific digital karyotyping (MSDK)......Page 144 Other sodium bisulfite based approaches......Page 146 MBD-affinity column (MAC)......Page 148 Methylated-CpG island recovery assay (MIRA)......Page 149 Future directions and challenges......Page 150 References......Page 151 Introduction......Page 158 Intermediate or Transient Heterochromatin......Page 159 Tri-methyl lysine 9 of histone H3 (H3K9me3) and cell cycle......Page 160 H3K9me3 and cancer......Page 162 References......Page 164 Introduction......Page 167 Features of the epigenome......Page 168 Epigenome during differentiation......Page 171 Cancer epigenome......Page 173 Physical organization of the genome......Page 174 References......Page 176 ChIP-on-chip Technique......Page 181 ChIP-on-chip Data Processing......Page 182 Calculation Algorithms for Epigenetic Data Extraction from ChIP-Seq Experiments......Page 184 Epigenetics of CpG islands......Page 186 References......Page 187 Post-transcriptional gene silencing......Page 190 Quelling in N. crassa......Page 191 Meiotic silencing by unpaired DNA in N. crassa......Page 192 PTGS in other filamentous fungi......Page 193 PTGS in protists......Page 194 RNA mediated development in ciliates......Page 195 Methylation induced premeioticaly in A. immersus ......Page 196 Repeat induced point mutation in N. crassa......Page 198 Chromatin-based regulation of secondary metabolite gene cluster expression......Page 199 Conclusion......Page 200 References......Page 201 Introduction......Page 208 The study of position effect variegation has led to the discovery of factors and structural proteins that constitute heterochromatin......Page 209 Heterochromatin formation involves a sequence of histone modifications......Page 212 RNA interference plays a critical role in heterochromatin formation......Page 213 Telomeric Heterochromatin......Page 214 The Unique Heterochromatin Attributes of Chromosome IV......Page 215 Modulation of Heterochromatin During Euchromatic Gene Transcription......Page 216 PcG Proteins form Regulatory Complexes......Page 217 The Binding of PcG Complexes Induces and Depends on Post-Translational Chromatin Modifications......Page 218 trxG regulatory proteins......Page 219 Interactions between PcG and trxG factors......Page 220 The MSL complex is responsible for dosage compensation......Page 221 Interaction with heterochromatin proteins......Page 222 H3.3 Replaces H3 in the Domain of Actively Transcribed Genes......Page 223 H2Av Participates in Gene Silencing......Page 224 Centromere-specific histone variants......Page 225 Insulators establish the boundaries of regulatory domains......Page 226 Insulators affect nuclear organization......Page 227 DNA methylation......Page 228 References......Page 229 Early exposures and adult disease: the mammalian model advantage......Page 241 Metastable epialleles......Page 242 The Axin Fused (AxinFu) Mouse Model......Page 243 The Mouse CDK5 Activator Binding Protein (CabpIAP) Metastable Epiallele......Page 244 Epigenetic Inheritance in Avy Mice......Page 246 The Avy and AxinFu Models and Methyl Donors......Page 248 The Avy Model and Isoflavones......Page 250 The Avy Model and Paternal Effect Genes......Page 251 Genomic imprinting......Page 252 The future of mouse models in epigenetic research......Page 254 References......Page 255 The plant epigenome......Page 258 The small RNAs in epigenetic regulation of silencing in plants......Page 259 Chromatin-based epigenetic mechanisms operating in transcriptional gene silencing (TGS)......Page 260 Rna-Dependent Rna Polymerases (Rdrs)......Page 261 RNA-directed DNA methylation (RdDM) of plant genomes......Page 262 Pol IV and Pol V......Page 263 Subunits and Partners of Pol IV and Pol V......Page 264 How are AGO and siRNAs Targeted to Specific Chromatin Sites?......Page 265 Transposable elements (TEs) and heterochromatin......Page 267 Epigenetic variations and plant evolution......Page 268 Paramutation......Page 269 Imprinting......Page 271 Genome Reprogramming During Flowering......Page 272 Polycomb group (PcG) and trithorax group (TrxG) complexes in plants......Page 273 Antagonistic PcG/TrxG Functions in Arabidopsis......Page 274 Chromatin remodeling......Page 275 Conclusions and perspectives......Page 276 References......Page 278 One-carbon metabolism and methyl donor production......Page 287 Regulation of SAM levels by precursor and cofactor bioavailability......Page 289 Homocysteine Metabolism......Page 291 Alcohol Antagonism of One-carbon Metabolism......Page 292 Mechanisms of DNA demethylation......Page 293 Cancer and One-carbon Deficiency......Page 294 References......Page 295 Introduction......Page 302 Histone acetylation......Page 305 Histone Deacetylases (HDACs)......Page 306 Histone Acetyltransferases (HATs)......Page 307 Histone methylation......Page 308 Conclusions......Page 313 References......Page 314 Stem cells......Page 321 DNA Methylation......Page 323 Acetylation......Page 325 Methylation......Page 326 Micro RNA......Page 328 Reprogramming for pluripotency......Page 329 References......Page 330 Epigenetic profile of muscle stem cells......Page 339 Genome reprogramming of muscle stem cells......Page 340 Transcriptional network that regulates adult skeletal myogenesis......Page 341 Chromatin-associated kinases: regulators of the epigenome in myogenic cells in response to regeneration cues......Page 342 Epigenetic regulation of skeletal myogenesis by miRNA......Page 343 Role of Individual miRNAs in Muscle Development ......Page 344 miR-27......Page 345 miRNAs and Muscular Dystrophies......Page 346 References......Page 347 Introduction......Page 352 Xist RNA as a key player in XCI......Page 353 Xist gene regulation......Page 355 Regulation of Xist by Pluripotency Related Factors......Page 356 Chromatin modifications characterizing the XCI......Page 357 Role of spatial organization within the nucleus in x inactivation......Page 358 References......Page 359 Introduction......Page 364 Imprint establishment and maintenance in mammals......Page 366 Replication Timing......Page 369 Histone modifications......Page 370 Chromatin Insulators......Page 371 Noncoding RNAs......Page 373 On the origin of genomic imprinting......Page 375 Organismic Models of Genomic Imprinting......Page 376 Mechanistic Models of Genomic Imprinting......Page 378 Reductionist Models of Genomic Imprinting......Page 380 Conclusion......Page 381 References......Page 382 Epigenetic modification of histones underlying memory......Page 391 Covalent modification of DNA underlying memory......Page 394 Summary......Page 397 References......Page 398 Introduction......Page 401 Epigenetic Consequences of Prenatal Maternal Exposures......Page 402 Postnatal Maternal Regulation of the Epigenome......Page 403 Paternal Influence on Offspring Development......Page 404 Germline-mediated Transgenerational Inheritance......Page 405 Experience-dependent Transgenerational Inheritance......Page 407 Epigenetics, Plasticity and Evolving Concepts of Inheritance......Page 408 References......Page 409 Introduction......Page 414 Dynamics of DNA Methylation During Aging......Page 415 Global Methylation Changes in Aging Cells......Page 416 Gene-Specific Methylation Changes......Page 417 One-Carbon Metabolism in Aging......Page 418 Histone Modifications During Aging......Page 420 Sirtuins......Page 421 Epigenetic Control of Telomeres in Aging......Page 422 Other Epigenetic Mediators that Influence Longevity......Page 423 Model of age-dependent epigenetic drift......Page 424 Lessons From Twin Research......Page 426 Conclusions and future directions......Page 427 References......Page 428 Practical Indications of Epigenetics......Page 435 Environment and Evolution......Page 436 Evolutionary concepts from the 19th century to today......Page 437 Evidence – Epidemiological, Transgenerational, and Molecular......Page 438 Inorganic Matter to Cellular Life......Page 439 Further Key Transitions in Evolution With Likely Changes in Epigenetic Processes......Page 440 Relationship in evolution between genetic changes and epigenetic......Page 441 Bacteria and mitochondria......Page 442 Mammals – transitions to placenta, live birth, and genomic imprinting......Page 443 Imprinting differences in the mammalian embryo and placenta......Page 444 Stability of the original chromatin strand in differentiating cells......Page 445 Origins of health and disease – primacy of epigenetics......Page 446 Physiological stages of imprinting processes......Page 447 Continuing evolutionary impacts on health and disease......Page 448 Mental disorders and heritability, and psychotic drug effects......Page 449 In conclusion......Page 450 References......Page 451 Introduction......Page 456 Maternal protein restriction model......Page 457 Nutrients involved in ONE-carbon metabolism......Page 458 Other nutrients......Page 459 Effects of diet on epigenetic states and disease in adulthood......Page 460 Folate, diseases, and epigenetics......Page 462 References......Page 463 Nickel......Page 468 Arsenic......Page 469 Chromium......Page 470 Cadmium......Page 471 Selenium......Page 472 Peroxisome proliferators......Page 473 Radiation......Page 474 Tobacco smoke......Page 475 Endocrine disruptors......Page 476 Polycyclic aromatic hydrocarbons......Page 477 Conclusion......Page 478 References......Page 481 Introduction......Page 486 Infections and epigenetic modifications......Page 488 Virus......Page 489 Chronic Inflammation......Page 491 Virus and epigenetics: role in cancer development......Page 492 Bacterial influence on the cell cycle......Page 493 Helicobacter pylori Infection and the Stomach......Page 494 Epigenetics and Microbial Infection in Colorectal Cancer......Page 496 Potential therapeutic implications......Page 498 References......Page 499 Introduction......Page 507 The Ad12-Hamster Cell System......Page 508 De Novo Methylation – An Ancient Cellular Defense System?......Page 509 Integration of Foreign DNA Can Alter Cellular Methylation Patterns at Sites Remote From the Insertion Locus......Page 510 Methylation Boundary at Equivalent Site in the Mouse Genome......Page 511 Isolated Unmethylated CpG Dinucleotides in De Novo Methylated DNA......Page 512 Proteins Binding at the Boundary Sequence in the Human FMR1 5'-Upstream Region......Page 513 The Epigenetic Profile of the Ad12 Integrates......Page 514 Viral Gene Activities in the Integrates......Page 516 Outlook......Page 517 References......Page 518 Epigenetic biomarkers......Page 524 Patients with drug-resistant cancer......Page 525 Nutritional aspects of population pharmacoepigenomics......Page 526 Effects of age and gender on pharmacoepigenomics......Page 527 References......Page 528 Mechanisms of epigenetic control in cancer......Page 531 Histone Modifications......Page 532 Epigenetics and oncogenesis......Page 533 Epigenetic Changes in “Normal” Stromal Cells of the Tumor Microenvironment......Page 534 Epigenetic Changes and Malignant Transformation......Page 535 Epigenetic Changes Associated with the Metastatic Phenotype......Page 536 Epigenetic diagnosis and prognosis......Page 537 Epigenetic therapy of cancer......Page 538 Conclusion......Page 539 References......Page 540 Innate Immunity......Page 545 Autoimmunity......Page 546 B Cells......Page 547 Epigenetics of SLE......Page 548 Epigenetics of RHEuMATOId ARTHRITIS (RA)......Page 550 Type 1 Diabetes Mellitus......Page 552 Systemic Sclerosis......Page 553 Use of epigenetic modifiers for potential diagnosis and therapy in autoimmune diseases......Page 554 References......Page 555 Introduction......Page 562 Epigenetic dysregulation in neurodevelopmental disorders – The example of Rett syndrome......Page 563 Epigenetic dysregulation in neurodegenerative disorders – The example of Alzheimer’s disease......Page 565 Epigenetic dysregulation in psychiatric disorders – The example of depression......Page 567 Epigenetic dysregulation in psychotic disorders – The example of schizophrenia......Page 569 Epigenetic dysregulation by environmental stress – The example of early life stress......Page 570 Conclusions and outlook......Page 571 References......Page 572 Etiological Factors in Metabolic Syndrome, Type 1 and Type 2 Diabetes Susceptibility......Page 578 Epigenetic Mechanism Underlying Genetic Susceptibility to Metabolic Diseases......Page 579 Influence of the in utero environment on epigenetic modification......Page 581 Epigenetic dysregulation of energy metabolism......Page 583 Epigenetic dysregulation of inflammation......Page 584 Potential therapeutic interventions involving epigenetic regulation......Page 585 References......Page 586 Introduction......Page 591 Uniparental Disomy (UPD)......Page 593 Imprinting Defects......Page 595 General aspects of IDs......Page 597 Beckwith–Wiedemann syndrome/BWS – chromosome 11......Page 598 Maternal and paternal UPD(14) syndromes/UPD(14)mat/pat – chromosome 14......Page 599 Genetic testing for IDs......Page 600 References......Page 601 Introduction......Page 605 Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA)......Page 607 Valproic Acid......Page 608 Entinostat (MS-275, SND-275)......Page 610 HDAC Inhibitors as a Single-Agent Therapy of Solid Tumors......Page 611 Combination Therapy with HDAC Inhibitors in the Treatment of Solid Tumors......Page 612 Phenylbutyrate......Page 614 Clinical Evaluation of Valproic Acid and Phenylbutyrate......Page 615 Current Clinical Trials Underway Evaluating HDAC Inhibitors for the Treatment of Non-Cancer Diseases......Page 616 Conclusion and the future direction of the clinical applications of HDAC inhibitors......Page 617 References......Page 618 Index......Page 624