METHODS IN ENZYMOLOGY: CHROMATIN STRUCTURE AND GENE REGULATION
1 Eukaryotic Gene Expression by RNA Polymerase II 1 11 Introduction 1 12 Transcriptional Initiation of RNA Polymerase II Genes 1 13 Transcriptional Elongation of RNA Polymerase II Genes 5 14 Transcriptional Termination of RNA Polymerase II Gene 8 15 Capping of mRNA at the 5´-End 9 16 Processing of mRNA at the 3´-End 10 17 Splicing of mRNA 11 18 Nuclear Export of mRNA for Translation 13 19 Conclusion 17 References 17 2 Epigenetic Code: Histone Modification, Gene Regulation, and Chromatin Dynamics 29 21 Introduction 29 22 Histone Modifications 31 221 Histone Acetylation and Deacetylation 31 222 Histone Lysine Methylation 33 2221 Histone H3K4-Specific Methylases 34 2222 H3K9-Specific Histone Methylases 35 2223 H3K27-Specific Methylases 35 2224 H3K36-Methylases 36 2225 H4K20-Specfic Methylases 37 2226 H3K79-Methylases 37 23 Histone Lysine Demethylation 38 24 Histone Arginine Methylation 39 25 Histone Phosphorylation and Dephosphorylation 40 26 Histone ADP-Ribosylation 42 27 Histone Ubiquitination 43 28 “Epigenetic Code” Hypothesis and Conclusion 44 Acknowledgments 48 List of Abbreviations 48 References 49 3 Histone Lysine Methylation, Demethylation, and Hormonal Gene Regulation 59 31 Introduction 59 32 The Enzymes That Catalyze Histone Lysine Methylation and Demethylation 60 321 Lysine Methyltransferases (KMTs) 61 3211 KMT1 Family 61 3212 KMT2 Family 71 3213 KMT3 Family 72 3214 KMT4 Family 73 3215 KMT5 Family 73 3216 KMT6 Family 73 3217 KMT7 Family 73 3218 KMT8 Family 74 3219 Unclassified KMTs 74 322 Lysine Demethylases (KDMs) 75 3221 KDM1 Family 75 3222 KDM2 Family 75 3223 KDM3 Family 76 3224 KDM4 Family 76 3225 KDM5 Family 76 3226 KDM6 Family 77 3227 KDM7 Family 77 3228 KDM8 Family 77 3229 Unclassified KDMs 78 33 Histone Lysine Methylation in Hormone Signaling 78 331 Hormone Receptor Classification 78 332 Estrogen Receptor-Like Subfamily 80 3321 Estrogen Receptor ? 80 3322 Androgen Receptor 83 3323 Other ER-Like Receptors 84 333 Thyroid Hormone Receptor-Like Subfamily 85 334 Retinoid X Receptor-Like Subfamily 86 335 Nerve Growth Factor 1B-Like Subfamily 87 336 Steroidogenic Factor-Like Subfamily 87 34 Perspectives 87 Acknowledgments 88 Abbreviations 88 References 89 4 The Role of HATs and HDACs in Cell Physiology and Disease 101 41 Introduction 101 42 HATs and HDACs 102 421 HATs 102 4211 HAT Complexes 103 422 HDACs 104 4221 HDAC Complexes in Transcription 105 43 Acetylation/Deacetylation in Chromatin-Associated Functions 107 431 HATs, HDACs, and Transcription 107 4311 Interplay between HATs/HDACs and Transcription Factors 108 432 Chromatin Structure and Heterochromatin 110 433 HATs and HDACs in DNA Repair 111 44 HATs and HDACs in Cell Physiology 113 441 Cell-Cycle Regulation 113 442 Apoptosis, Aging, and Senescence 115 443 Differentiation and Development 117 4431 Stem Cells 117 4432 Embryonic Lethality and Early Development 117 4433 Myogenesis and Osteogenesis 118 4434 Heart Development, Angiogenesis, and Kidney Development 118 4435 Adipose Tissue 119 4436 Nervous System Development 119 4437 Hematopoiesis 120 444 Metabolism 120 4441 Lipid Metabolism 121 4442 Glucose Metabolism 121 4443 Other Mitochondrial Processes 122 4444 FOXO and Metabolism 122 45 Associated Diseases 122 451 Cancer 123 4511 Leukemias 125 4512 Breast Cancer 125 4513 Other Cancers 125 4514 Metastasis 126 452 Vascular Diseases 126 453 Neurodegenerative Diseases 127 454 Other Diseases 127 References 127 5 The Short and Medium Stories of Noncoding RNAs: microRNA and siRNA 137 51 Introduction 137 52 MicroRNA 140 521 Discovery of miRNAs 140 522 Biogenesis of miRNA 141 523 Processing of miRNA and its Mechanism of Action 141 524 Functional Significance of miRNA 144 5241 Hormone Synthesis and Metabolism 146 5242 Immune System 147 5243 Reproduction 147 525 Association of miRNAs with Human Diseases and Cancer 148 53 Small Interfering RNA (siRNA) 151 531 Discovery of siRNAs 151 532 Biogenesis of siRNAs 152 533 Processing and Mechanism of Action of siRNAs 153 54 Piwi interacting RNA 154 55 Transcription Initiating RNAs (TiRNAs) 155 56 Small Nuclear RNAs (snRNAs) 155 57 Conclusion 156 Acknowledgments 157 Abbreviations 157 References 157 6 Long Noncoding RNA (lncRNA): Functions in Health and Disease 169 61 Introduction 169 62 Classification of lncRNAs 170 63 LncRNA: Functions and Mechanisms of Action 171 631 LncRNA XIST and TSIX in Dosage Compensation and X-Inactivation 172 632 HOTAIR (HOX Antisense Intergenic lncRNA) in Gene Silencing 172 633 H19: Important in Genomic Imprinting and microRNA Biogenesis 175 634 ANRIL: Transcriptional Regulation of INK4A Locus 177 635 GAS5: Associated with Growth and Glucocorticoid Receptor-Mediated Signaling 177 636 TERRA (Telomeric Repeat-Containing RNAs) in Telomere Function 178 637 MEG3: Important Player in Genomic Imprinting 179 638 KCNQ1OT1/LIT1: Key Player in Genomic Imprinting 179 639 MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) 180 6310 PCAT1 180 6311 PCGEM1 180 64 LncRNAs in Cancer 181 65 LncRNAs in Reproduction 185 66 LncRNAs in Myogenesis 187 67 LncRNA in Cardiovascular Disease 189 68 LncRNAs in Embryonic Development and Segmentation 190 69 LncRNA in Central Nervous System 190 610 LncRNAs in Neurological Disorders 191 61011 Importance of ATXN8OS in Spinocerebellar Ataxia 8 192 61012 Role of DISC1 and DISC2 in Schizophrenia and Neuronal Hyperexcitability 192 61013 UBE3A-AS in Prader–Willi Syndrome (PWS) and Angelman Syndrome 193 611 LncRNA in Immune System and Immunological Disorders 193 612 Roles of lncRNAs in Various Heritable Syndromes 194 613 Conclusion 195 Acknowledgments 196 Abbreviations 196 References 197 7 Histone Variants: Structure, Function, and Implication in Diseases 209 71 Histone Variants: Structure 209 711 Histone Proteins Have Sequence Variants 209 712 Histones are Posttranslationally Modified 211 713 Nucleosome Structure 213 7131 Histone H2A Variants 214 7132 Histone H3 Variants 218 72 Implication in Diseases 219 Acknowledgments 221 References 221 8 Genomic Imprinting in Mammals: Origin and Complexity of an Epigenetically Regulated Phenomenon 227 81 Introduction: First Evidences and Extent of Genomic Imprinting 227 811 The Discovery of Imprinted Gene Expression 227 812 How Many Imprinted Genes? 228 82 Imprinted Genes: Common Features and Diversity of Regulatory Mechanisms 229 821 Imprinted Domains and the Elements That Control Them 229 822 Imprinted Expression Can Be Regulated in Multiple Ways 231 83 Role of Imprinted Noncoding RNAs on Imprinting Control and Other Functions 233 84 Parent-of-Origin-Dependent Epigenetic Marks and the Role of Chromatin Modifications and Interactions in Imprinting 234 841 Origin and Function of Differentially Methylated Regions in Imprinted Domains 234 842 The Contribution of Histone Modifications to Imprinting Control 237 843 Nuclear Location and Diverse Types of Interactions May also Play a Role in the Regulation of Imprinted Genes 237 85 Imprinted Genes: Functions and Associated Diseases 238 851 Mutations and Epimutations of Imprinted Loci Result in Diverse Disorders 238 852 Consequences of Loss of Imprinting 239 86 Origin and Evolution of Imprinting 241 861 Why Is There Imprinting? 241 862 When and How Did Imprinted Expression Emerge at Diverse Genes? 244 87 Summary and Conclusion 246 Acknowledgments 247 References 247 9 Centromere and Kinetochore: Essential Components for Chromosome Segregation 259 91 Introduction 259 911 Distinguishing Features of Mitosis 261 9111 Fungi 261 9112 Animals 261 9113 Plants 261 9114 Protozoa 262 92 Centromeres 262 921 Diversity in Organization of DNA Elements Across Centromeres 263 9211 Fungi 263 9212 Animals 266 9213 Plants 267 9214 Protozoa 268 93 Kinetochores 269 931 Kinetochore Architecture 270 932 Centromere DNA-Associated Layer 270 9321 Constitutive Centromere-Associated Network (CCAN) 270 933 Microtubule Interacting Layer 272 9331 KMN Network 272 934 Kinetochore Assembly 273 9341 Fungi 273 9342 Animals 274 9343 Plants 275 9344 Protozoa 275 94 Neocentromere 276 941 Naturally Occurring Neocentromeres 276 9411 Humans 276 9412 Plants 277 942 Artificially Induced Neocentromeres 277 9421 Fungi 277 9422 Animals 278 943 Factors Relating to Neocentromere/Centromere Formation 278 9431 Centromere-Associated Proteins 278 9432 Chromatin 278 9433 Replication Timing 278 95 Conclusions 279 Acknowledgment 280 References 280 10 Nuclear Receptors and NR-coregulators: Mechanism of Action and Cell Signaling 289 101 Introduction 289 102 Structures of Nuclear Receptors 292 103 Mode of Action of Nuclear Receptors 295 104 Nuclear Receptor Coregulators 297 1041 NR-Coactivators 298 10411 ATP-Dependent Chromatin Remodelers 298 10412 Histone Acetyltransferases 299 10413 Histone Methyltransferases and Demethylases in NR-Regulated Gene Expression 301 10414 Histone Demethylase 302 10415 PGC-1? (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha) as NR-Coactivator 306 10416 Proline-, Glutamic Acid-, Leucine-Rich Protein 1 (PELP1) as NR-Coactivator 306 1042 Corepressors 306 1043 Noncoding RNA (ncRNA) as NR-Coregulators 308 105 NRs and NR-Coregulators in Human Diseases 308 106 NRs and NR-Coregulators as Drug Targets 310 107 Conclusion 313 Acknowledgments 313 Abbreviations 313 References 314 11 Estrogen and Progesterone Receptor Signaling and Action 329 111 Introduction 329 112 Nuclear Hormone Receptor Superfamily 330 113 Estrogen and Progesterone Receptor Isoforms 332 114 Mechanisms of Estrogen and Progesterone Signaling 334 1141 Direct Genomic Signaling (Ligand Dependent) 335 1142 Indirect Genomic Signaling – Ligand Independent 336 1143 Nongenomic Signaling – Membrane Steroid Receptors 336 11431 Nongenomic Estrogen Signaling 337 11432 Nongenomic Progesterone Signaling 338 115 Integration of Membrane and Nuclear Signaling 338 116 Coregulators of Estrogen and Progesterone Signaling 338 1161 The p160 Steroid Receptor Coactivator Family 339 1162 Corepressors of Steroid Hormone Receptors 342 117 Convergence of ER and PR Signaling Mechanisms: Focus on the Brain 342 1171 Expression and Distribution of Corepressors in the Brain 345 118 Conclusion 345 References 345 12 Gonadal Steroid Hormones and Brain Protection 355 121 Introduction 355 122 The Protective Effects of Estrogens on the Brain 355 123 The Protective Effects of Progesterone on the Brain 356 124 The Protective Effects of Androgens in the Brain 359 125 Clinical Studies of Estrogens in Alzheimer’s Disease 361 126 Clinical Studies Addressing the Protective Effects of Progesterone and Related Progestins 362 127 Clinical Studies Addressing the Potential Beneficial Effects of Androgens 364 128 Conclusions 365 References 366 13 Glucocorticoid Receptor-Mediated Signaling and Stress Metabolism 377 131 Introduction 377 132 Gene Regulation 378 1321 History of the GR 378 1322 Overall Structure 378 1323 Glucocorticoid Response Elements (GREs) 379 13231 Activating GREs, Palindromes 379 13232 Negative GREs (nGREs) 380 13233 Bioinformatic Contributions 381 1324 Coregulators 381 13241 Coactivators 381 13242 Corepressors 382 13243 Coregulators with Activating and Repressing Activities 383 1325 Chromatin Remodeling 383 1326 Structural Analysis of GR 384 13261 Crystal Structures 384 1327 Summary 385 133 Metabolism 385 1331 PEPCK Promoter Mapping 386 13311 GR Binding Sites 387 13312 Other TF Binding Sites 387 1332 Role of Coactivators 387 13321 Mechanisms of PEPCK Repression 388 13322 PEPCK Chromatin 388 13323 Metabolic Network 388 1333 Summary 388 134 The HPA Axis 389 1341 The CRH Promoter 389 1342 Methylated CpG Binding Protein 2 (MeCP2) 391 1343 Specificity 392 1344 Summary 393 135 Conclusion 393 References 394 14 Targeting Androgen Signaling in Prostate Cancer 399 141 Introduction 399 142 Disease States of Metastatic Prostate Cancer 400 143 Androgens and Androgen Receptor 401 144 Castrate-Sensitive Prostate Cancer 404 145 Prostate Cancer Progression 405 146 Prostate Cancer Drugs 407 1461 Blocking Androgen Production 407 1462 Blocking the Androgen Receptor 409 1463 Destabilizing the Androgen Receptor 410 1464 Modifying Androgen Receptor DNA 410 147 Future of Prostate Cancer Therapy 411 148 Conclusion 412 References 412 15 Role of Peroxisome Proliferator-Activated Receptors in Inflammation and Angiogenesis 417 151 Introduction 417 152 PPAR? (NR1C1) 432 1521 Inflammation 432 15211 Hepatic Inflammation 433 15212 Inflammation in Vascular Wall 433 15213 Inflammation in Spinal Cord 434 1522 Angiogenesis 434 15221 Anticancer/Antiangiogenic Activity 434 15222 Proangiogenic Activity 436 153 PPAR?/? (NR1C2) 436 1531 Inflammation 437 1532 Wound Healing 437 1533 Angiogenesis 438 15331 Proangiogenic Activity 438 1534 Antiangiogenic Activity 438 154 PPAR? (NR1C3) 439 1541 Inflammation 440 15411 Allergic Inflammation 440 15412 Viral Inflammation 440 15413 Neuroprotection/Inflammation-AZ/PD 441 15414 Atherosclerosis 441 1542 Angiogenesis 441 15421 Cornea and Retina 441 15422 Lung/Bone/Fat Tissue/Placenta 443 155 Concluding Remarks 443 References 444 16 RAR/RXR-Mediated Signaling 457 161 Introduction 457 162 Vitamin A Receptors and Their Response Elements 457 1621 RAR and RXR Ligands 459 1622 The Structure of Retinoid Receptors 461 1623 Retinoic Acid Response Elements 463 163 Transcriptional RAR/RXR Signaling: The Standard Model and Recent Discoveries 463 1631 Ligand Binding and Exchange of Cofactors 465 1632 Histone Modification and Recruitment of the Transcription Machinery 465 1633 Termination of RAR-Dependent Signaling 467 1634 New RAR Binding Sites 467 1635 Variations of the Classical Model of Activation 467 164 Regulation of RAR Signaling: Ligand Synthesis and Metabolism 468 1641 Cleavage of Provitamin A and Retinyl Esters 468 1642 Uptake of Dietary Retinol 470 1643 Synthesis of Retinal 470 1644 Synthesis of Retinoic Acid 471 1645 Retinoic Acid Degradation 471 165 Regulation of RAR Signaling: The Role of Binding Proteins 474 1651 Intestinal Uptake and Hepatic Storage 475 1652 Transport in the Circulation 476 1653 Cellular Uptake in Target Tissues 477 1654 Retinoic Acid Synthesis and Degradation 477 1655 Nuclear Receptor Activation 478 166 Regulation of RAR Signaling: Receptor Expression, Modification, and Degradation 479 1661 Specific Expression of RARs in the Body 479 1662 Nuclear Translocation 479 1663 Posttranslational Modification of RAR/RXR 481 167 Transrepression and Crosstalk with Other Transcription Factors 482 1671 Transrepression of Other Regulatory Sequences 483 1672 Interactions between RAR and Other Transcription Factors 483 1673 Transcriptional Control by Other Retinoids 484 168 Nongenomic Mechanisms of RA/RAR Signaling 485 1681 Rapid Physiological Effects of RA 486 1682 Cytosolic Localization of RAR 486 1683 Direct Interactions with Protein Kinases 487 1684 Suppression of Protein Translation 487 169 The Role of Retinoid Binding Proteins in Phototransduction 488 1691 The Retinoid Cycle of Phototransduction 488 1692 Phototransduction and the Evolution of RA Nuclear Signaling 490 1610 Retinoic acid-Regulated Genes 490 16101 Direct Gene Targets of RA 490 16102 Indirect Targets of RA 492 16103 Discrepancies between DNA Binding and Active Signaling 492 16104 “Systems Biology” of RA Signaling 493 1611 Conclusion 493 List of Abbreviations and Symbols 495 References 496 17 On the Trail of Thyroid Hormone Receptor Epigenetics 511 171 Introduction 511 1711 Brief Historical Background 511 1712 Functional Background 512 17121 Biosynthesis of Thyroid Hormones and Their Metabolites 512 17122 Thyroid Hormone Transportation 514 17123 Physiologic Pathway of Thyroid Hormone Secretion 515 172 Overview of Thyroid Hormone Action 517 1721 Molecular Mechanism of Thyroid Hormone Action 518 17211 Concepts of Cellular Thyroid Hormone Receptors 518 17212 Classification of the Nuclear Receptors for Thyroid Hormones and Their Isoforms 518 17213 Thyroid Hormone Receptor Functional Domains 522 17214 Thyroid Response Elements (TREs) 524 173 Molecular Mechanisms of Regulation of Gene Expression by Thyroid Hormone-Specific Nuclear Receptors 526 174 Nongenomic Mechanism of Action of Thyroid Hormones 530 175 Conclusion 533 References 534 18 Insulin Signaling, Epigenetics, and Human Diseases 541 181 Introduction to Epigenetics 541 182 Types of Epigenetic Modifications 542 1821 Histone Acetylation/Deacetylation 542 1822 DNA–Histone Methylation/Demethylation 543 1823 Histone Phosporylation and O-Linked N-Acetylglucosamination 545 183 Epigenetic Links to Endocrine System 545 184 Insulin 546 1841 Epigenetic Pattern of Ins Gene 547 1842 Glucose-Induced Chromatin Modification in Ins Gene Promoter 549 1843 Epigenetics Related to Insulin Biosynthesis 549 185 Insulin Signaling 552 186 Insulin Receptor 553 1861 Regulation of Insulin Receptor 553 18611 Genetic Regulation 554 18612 Epigenetic Regulation 554 18613 Hormonal Regulation 555 187 Insulin Receptor Substrate (IRS) 555 1871 Epigenetics Involved with IRS 555 188 The PI(3)K Pathway 556 1881 Epigenetics Involved with PI(3)K/AKT 557 1882 Epigenetics Involved with GSK3 (Glycogen Synthase Kinase 3) 557 1883 Epigenetics Involved with Glucose Transporters 558 189 The Ras Pathway 559 1891 Epigenetics Involved in Ras Pathway 560 1810 Insulin Resistance and Metabolic Derangements 560 18101 Insulin Resistance and Epigenetics 561 18102 Insulin Resistance, Metabolic Derangements, and Chromatin Remodeling 563 1811 Conclusion 564 Acknowledgment 565 Abbreviations 565 Function of the Genes Discussed in this Chapter 566 References 567 19 Endocrine Disruptors and Epigenetics 577 191 Introduction 577 192 Endocrine Disruptors 582 1921 Bisphenol-A 582 1922 Diethylstilbestrol 583 1923 Phthalates 584 19231 Di(2-Ethylhexyl) Phthalate (DEHP) 584 19232 Di-n-Butyl Phthalate (DBP) 584 19233 Benzyl Butyl Phthalate (BBzP or BBP) 584 1924 Vinclozolin 585 1925 Perfluorooctanoic Acid (PFOA) 585 193 Associated Diseases 586 1931 Systemic Lupus Erythematosus (SLE) 586 1932 Diabetes and Obesity 587 1933 Neuroendocrine-Associated Pathophysiology 590 1934 Cancer 592 1935 Effects on Reproduction 594 194 Endocrine Disruptors and Development of Transgenerational Disease 596 195 Discussion 597 References 597 20 Endocrine Disruptors: Mechanism of Action and Impacts on Health and Environment 607 201 Introduction 607 202 Mechanism of Action of EDC 611 2021 Interference in Nuclear Receptor-Mediated Cell Signaling 611 2022 Alternation in Epigenetics by EDCs 613 203 Bisphenol A (BPA) and its Health Impacts 613 2031 Molecular Mechanism of Action of BPA 614 2032 Health Impacts of BPA 615 204 Diethylstilbestrol (DES) 616 2041 Mechanism of Action of DES 617 2042 Health Impacts of DES 618 205 Atrazine 619 2051 Mechanism of Action and Health Impacts of Atrazine 619 206 Polychlorinated Biphenyls (PCBs) 620 2061 Health Defects Caused by PCBs and Potential Mechanism 620 207 Phthalates 621 2071 Health Defects Caused by Phthalates 622 208 Phytoestrogens 622 209 Methoxychlor 624 2091 Health Impacts by Methoxychlor 625 2010 Dioxins: An Environmental Contaminant 625 2011 Conclusion 626 Acknowledgments 627 Abbreviations 627 References 628