GENE REGULATION, EPIGENETICS AND HORMONE SIGNALING

Volume I
1 Eukaryotic Gene Expression by RNA Polymerase II 1
1.1 Introduction 1
1.2 Transcriptional Initiation of RNA Polymerase II Genes 1
1.3 Transcriptional Elongation of RNA Polymerase II Genes 5
1.4 Transcriptional Termination of RNA Polymerase II Gene 8
1.5 Capping of mRNA at the 5´-End 9
1.6 Processing of mRNA at the 3´-End 10
1.7 Splicing of mRNA 11
1.8 Nuclear Export of mRNA for Translation 13
1.9 Conclusion 17
References 17
2 Epigenetic Code: Histone Modification, Gene Regulation, and Chromatin Dynamics 29
2.1 Introduction 29
2.2 Histone Modifications 31
2.2.1 Histone Acetylation and Deacetylation 31
2.2.2 Histone Lysine Methylation 33
2.3 Histone Lysine Demethylation 38
2.4 Histone Arginine Methylation 39
2.5 Histone Phosphorylation and Dephosphorylation 40
2.6 Histone ADP-Ribosylation 42
2.7 Histone Ubiquitination 43
2.8 “Epigenetic Code” Hypothesis and Conclusion 44
Acknowledgments 48
List of Abbreviations 48
References 49
3 Histone Lysine Methylation, Demethylation, and Hormonal Gene Regulation 59
3.1 Introduction 59
3.2 The Enzymes That Catalyze Histone Lysine Methylation and Demethylation 60
3.2.1 Lysine Methyltransferases (KMTs) 61
3.2.2 Lysine Demethylases (KDMs) 75
3.3 Histone Lysine Methylation in Hormone Signaling 78
3.3.1 Hormone Receptor Classification 78
3.3.2 Estrogen Receptor-Like Subfamily 80
3.3.3 Thyroid Hormone Receptor-Like Subfamily 85
3.3.4 Retinoid X Receptor-Like Subfamily 86
3.3.5 Nerve Growth Factor 1B-Like Subfamily 87
3.3.6 Steroidogenic Factor-Like Subfamily 87
3.4 Perspectives 87
Acknowledgments 88
Abbreviations 88
References 89
4 The Role of HATs and HDACs in Cell Physiology and Disease 101
4.1 Introduction 101
4.2 HATs and HDACs 102
4.2.1 HATs 102
4.2.2 HDACs 104
4.3 Acetylation/Deacetylation in Chromatin-Associated Functions 107
4.3.1 HATs, HDACs, and Transcription 107
4.3.2 Chromatin Structure and Heterochromatin 110
4.3.3 HATs and HDACs in DNA Repair 111
4.4 HATs and HDACs in Cell Physiology 113
4.4.1 Cell-Cycle Regulation 113
4.4.2 Apoptosis, Aging, and Senescence 115
4.4.3 Differentiation and Development 117
4.4.4 Metabolism 120
4.5 Associated Diseases 122
4.5.1 Cancer 123
4.5.2 Vascular Diseases 126
4.5.3 Neurodegenerative Diseases 127
4.5.4 Other Diseases 127
References 127
5 The Short and Medium Stories of Noncoding RNAs: microRNA and siRNA 137
5.1 Introduction 137
5.2 MicroRNA 140
5.2.1 Discovery of miRNAs 140
5.2.2 Biogenesis of miRNA 141
5.2.3 Processing of miRNA and its Mechanism of Action 141
5.2.4 Functional Significance of miRNA 144
5.2.5 Association of miRNAs with Human Diseases and Cancer 148
5.3 Small Interfering RNA (siRNA) 151
5.3.1 Discovery of siRNAs 151
5.3.2 Biogenesis of siRNAs 152
5.3.3 Processing and Mechanism of Action of siRNAs 153
5.4 Piwi interacting RNA 154
5.5 Transcription Initiating RNAs (TiRNAs) 155
5.6 Small Nuclear RNAs (snRNAs) 155
5.7 Conclusion 156
Acknowledgments 157
Abbreviations 157
References 157
6 Long Noncoding RNA (lncRNA): Functions in Health and Disease 169
6.1 Introduction 169
6.2 Classification of lncRNAs 170
6.3 LncRNA: Functions and Mechanisms of Action 171
6.3.1 LncRNA XIST and TSIX in Dosage Compensation and X-Inactivation 172
6.3.2 HOTAIR (HOX Antisense Intergenic lncRNA) in Gene Silencing 172
6.3.3 H19: Important in Genomic Imprinting and microRNA Biogenesis 175
6.3.4 ANRIL: Transcriptional Regulation of INK4A Locus 177
6.3.5 GAS5: Associated with Growth and Glucocorticoid Receptor-Mediated Signaling 177
6.3.6 TERRA (Telomeric Repeat-Containing RNAs) in Telomere Function 178
6.3.7 MEG3: Important Player in Genomic Imprinting 179
6.3.8 KCNQ1OT1/LIT1: Key Player in Genomic Imprinting 179
6.3.9 MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) 180
6.3.10 PCAT1 180
6.3.11 PCGEM1 180
6.4 LncRNAs in Cancer 181
6.5 LncRNAs in Reproduction 185
6.6 LncRNAs in Myogenesis 187
6.7 LncRNA in Cardiovascular Disease 189
6.8 LncRNAs in Embryonic Development and Segmentation 190
6.9 LncRNA in Central Nervous System 190
6.10 LncRNAs in Neurological Disorders 191
6.11 LncRNA in Immune System and Immunological Disorders 193
6.12 Roles of lncRNAs in Various Heritable Syndromes 194
6.13 Conclusion 195
Acknowledgments 196
Abbreviations 196
References 197
7 Histone Variants: Structure, Function, and Implication in Diseases 209
7.1 Histone Variants: Structure 209
7.1.1 Histone Proteins Have Sequence Variants 209
7.1.2 Histones are Posttranslationally Modified 211
7.1.3 Nucleosome Structure 213
7.2 Implication in Diseases 219
Acknowledgments 221
References 221
8 Genomic Imprinting in Mammals: Origin and Complexity of an Epigenetically Regulated Phenomenon 227
8.1 Introduction: First Evidences and Extent of Genomic Imprinting 227
8.1.1 The Discovery of Imprinted Gene Expression 227
8.1.2 How Many Imprinted Genes? 228
8.2 Imprinted Genes: Common Features and Diversity of Regulatory Mechanisms 229
8.2.1 Imprinted Domains and the Elements That Control Them 229
8.2.2 Imprinted Expression Can Be Regulated in Multiple Ways 231
8.3 Role of Imprinted Noncoding RNAs on Imprinting Control and Other Functions 233
8.4 Parent-of-Origin-Dependent Epigenetic Marks and the Role of Chromatin Modifications and Interactions in Imprinting 234
8.4.1 Origin and Function of Differentially Methylated Regions in Imprinted Domains 234
8.4.2 The Contribution of Histone Modifications to Imprinting Control 237
8.4.3 Nuclear Location and Diverse Types of Interactions May also Play a Role in the Regulation of Imprinted Genes 237
8.5 Imprinted Genes: Functions and Associated Diseases 238
8.5.1 Mutations and Epimutations of Imprinted Loci Result in Diverse Disorders 238
8.5.2 Consequences of Loss of Imprinting 239
8.6 Origin and Evolution of Imprinting 241
8.6.1 Why Is There Imprinting? 241
8.6.2 When and How Did Imprinted Expression Emerge at Diverse Genes? 244
8.7 Summary and Conclusion 246
Acknowledgments 247
References 247
9 Centromere and Kinetochore: Essential Components for Chromosome Segregation 259
9.1 Introduction 259
9.1.1 Distinguishing Features of Mitosis 261
9.2 Centromeres 262
9.2.1 Diversity in Organization of DNA Elements Across Centromeres 263
9.3 Kinetochores 269
9.3.1 Kinetochore Architecture 270
9.3.2 Centromere DNA-Associated Layer 270
9.3.3 Microtubule Interacting Layer 272
9.3.4 Kinetochore Assembly 273
9.4 Neocentromere 276
9.4.1 Naturally Occurring Neocentromeres 276
9.4.2 Artificially Induced Neocentromeres 277
9.4.3 Factors Relating to Neocentromere/Centromere Formation 278
9.5 Conclusions 279
Acknowledgment 280
References 280
10 Nuclear Receptors and NR-coregulators: Mechanism of Action and Cell Signaling 289
10.1 Introduction 289
10.2 Structures of Nuclear Receptors 292
10.3 Mode of Action of Nuclear Receptors 295
10.4 Nuclear Receptor Coregulators 297
10.4.1 NR-Coactivators 298
10.4.2 Corepressors 306
10.4.3 Noncoding RNA (ncRNA) as NR-Coregulators 308
10.5 NRs and NR-Coregulators in Human Diseases 308
10.6 NRs and NR-Coregulators as Drug Targets 310
10.7 Conclusion 313
Acknowledgments 313
Abbreviations 313
References 314

Volume II
11 Estrogen and Progesterone Receptor Signaling and Action 329
12 Gonadal Steroid Hormones and Brain Protection 355
13 Glucocorticoid Receptor-Mediated Signaling and Stress Metabolism 377
14 Targeting Androgen Signaling in Prostate Cancer 399
15 Role of Peroxisome Proliferator-Activated Receptors in Inflammation and Angiogenesis 417
16 RAR/RXR-Mediated Signaling 457
17 On the Trail of Thyroid Hormone Receptor Epigenetics 511
18 Insulin Signaling, Epigenetics, and Human Diseases 541
19 Endocrine Disruptors and Epigenetics 577
20 Endocrine Disruptors: Mechanism of Action and Impacts on Health and Environment 607
Index 639

The first of its kind, this reference gives a comprehensive but concise introduction to epigenetics before covering the many interactions between hormone regulation and epigenetics at all levels. The contents are very well structured with no overlaps between chapters, and each one features supplementary material for use in presentations. Throughout, major emphasis is placed on pathological conditions, aiming at the many physiologists and developmental biologists who are familiar with the importance and mechanisms of hormone regulation but have a limited background in epigenetics.

Author
Subhrangsu S. Mandal is currently Associate Professor at the Department of Chemistry and Biochemistry, at The University of Texas at Arlington, Texas. He received his PhD degree from the Indian Institute of Science, Bangalore, where he worked on chemical nucleases and cationic liposome-mediated gene delivery in the laboratory of Professor S. Bhattacharya. He joined the laboratory of Professor Linda J. Reha-Krantz as an Alberta Heritage Foundation for Medical Research (AHFMR) postdoctoral fellow in the University of Alberta, Canada. He later moved to the laboratory of Professor Danny Reinberg to research on eukaryotic transcription and gene regulation in human at the University of Medicine and Dentistry of New Jersey (UMDNJ)/Howard Hughes Medical Institute (HHMI). Prof. Mandal began his independent career at University of Texas at Arlington in 2005. Specifically he is investigating the function of Mixed Lineage Leukemia (MLL) family of histone methyl-transferases in gene activation, estrogen signalling, and tumorigenesis. In parallel, the Mandal laboratory is also developing novel gene targeted cancer therapy using mouse models.