Epigenetics and Human Reproduction (eBook)

Preface to the Series 6
Foreword 8
References 10
Contents 12
Contributors 14
Part I: Medical Aspects and Questions Raised on the Molecular Basis of Epigenome Involvement in Reproduction 18
Chapter 1: Potential Epigenetic Consequences Associated with Assisted Reproduction 19
1.1 Introduction 20
1.2 ARTs and the Timing of Epigenetic Events during Gametogenesis and Embryogenesis 20
1.2.1 Gamete Development 21
1.2.2 Preimplantation Embryo Development 22
1.3 Assisted Reproduction and Imprinting Disorders 22
1.4 Searching for Epigenetic Abnormalities in Children Conceived Using ARTs 24
1.5 Underlying Infertility as a Contributor to Imprinting Defects After ART 25
1.6 Techniques Used in ART and Imprinting Defects 27
1.7 Assisted Reproduction and Other Potential Epigenetic Effects 27
1.8 Lessons from Animal Models: Mimicking Techniques Used in Human-Assisted Reproduction 28
1.8.1 Superovulation and Gamete Manipulation 28
1.8.2 Embryo Culture 29
1.9 Future Directions 30
References 31
Chapter 2: Germ Cell Cancer, Testicular Dysgenesis Syndrome and Epigenetics 35
2.1 Introduction 36
2.2 Epigenetics in Testicular Development: From Specification of Primordial Gem Cells to Formation of the Gonads 36
2.3 TDS: A Collection of Reproductive Disorders with a Possible Common Pathogenesis 39
2.3.1 Testicular Cancer 39
2.3.2 Undescended Testis and Hypospadias 41
2.3.3 Impaired Spermatogenesis with Developmental Aetiology 41
2.4 Endocrine Disrupters and Their Possible Influence on Epigenetic Patterns 42
2.4.1 Evidence from Human Studies 42
2.4.2 Evidence from Studies in Animals 43
2.5 Epigenetics of Germ Cell Tumors and Testicular Dysgenesis 44
2.5.1 Chromatin Changes 44
2.5.2 Methylation Profiles of Specific Genes Important for Pluripotency and Tumorigenesis 46
2.5.3 X-Linked Genes and XIST Expression 47
2.5.4 Gene Imprinting 48
2.5.5 Possible Involvement of miRNAs in TGCTs and Neoplastic Transformation 50
2.6 Open Questions and Perspectives 51
References 52
Chapter 3: Medical Implications of Sperm Nuclear Quality 61
3.1 Fundamental Knowledge on Sperm Genome and Proteome/Epigenome Constitution 62
3.1.1 Changes in Sperm Nuclear Composition and Structure During Spermatogenesis 62
3.1.2 Sperm Cell Nuclear Proteome 64
3.1.3 Sperm Cell Epigenome 69
3.2 Approaches/Tests for Exploring Sperm Nuclear Quality in Human Infertility 72
3.2.1 Sperm DNA Quality and Integrity 72
3.2.2 Measurement of the Protamine Content in Infertile Patients 76
3.2.3 Correlation Between Protamines and Sperm DNA Integrity 79
3.3 Sperm Nuclear Quality and Outcome of ART 80
3.4 Present Limitations of Sperm Nuclear Quality Assessment and Open Questions 84
References 85
Chapter 4: Gene Expression/Phenotypic Abnormalities in Placental Tissues of Sheep Clones: Insurmountable Block in Cloning Progress? 100
4.1 Introduction 100
4.2 Abnormal Nuclear Reprogramming in Clones and Related Placental Phenotypes 102
4.3 Possible Directions to Improve SCNT 106
4.4 Concluding Remarks 108
References 109
Part II: Fundamental Aspects of Genome and Epigenome Reprogramming During Gametogenesis 112
Chapter 5: Epigenetic Reprogramming Associated with Primordial Germ Cell Development 113
5.1 Introduction 113
5.1.1 From Fertilization to the Specification of the New Germ Cell Lineage 114
5.2 A Brief Overview of the Epigenetic Reprogramming During PGC Development 116
5.3 The Cell Cycle State of PGCs 118
5.4 Genome-Wide DNA Demethylation in Migrating PGCs 119
5.5 Genome-Wide Demethylation of H3K9me2 in Migrating PGCs 120
5.6 Global Transcriptional Repression in Migrating PGCs 121
5.7 Genome-Wide Upregulation of H3K27me3 in Migrating PGCs 122
5.8 Arginine Methylation Mediated by Blimp1/Prmt5 Complex in Migrating PGCs 122
5.9 Potential Significance of Epigenetic Reprogramming in Migrating PGCs 123
5.10 Epigenetic Reprogramming of Imprinted Genes in Postmigrating PGCs 124
5.11 Modification of the Repetitive Elements in PGCs 125
5.12 Modification of the Specific Loci in PGCs 126
5.13 Conclusion 127
References 127
Chapter 6: Epigenetic Factors and Regulation of Meiotic Recombination in Mammals 132
6.1 Introduction 133
6.2 Outline of the Molecular Mechanism of Meiotic Recombination 134
6.3 How to Measure Recombination Activity in Mammals? 136
6.3.1 Pedigree Analysis 136
6.3.2 Sperm Typing 137
6.3.3 MLH1 Foci 137
6.3.4 Population Diversity Analysis 137
6.4 Indirect Evidence that Epigenetic Modifications Influence Recombination Activity in Mammals 138
6.4.1 Male Versus Female Recombination 138
6.4.1.1 Male and Female Genetic Maps 138
6.4.1.2 Recombination Activities in Minisatellites 142
6.4.1.3 Regions Subjected to Parental Imprinting 142
6.4.1.4 CO Frequency and Length of the Synaptonemal Complex 143
6.4.2 Interindividual Variations 143
6.4.2.1 Variations in Genome Wide CO Rates 144
6.4.2.2 Variations of Hotspot Activity in Humans 144
6.4.2.3 Variations of Hotspot Activity in Mice 146
6.5 Evidence for Epigenetic Modifications During Meiosis and Genes Known to Regulate such Modifications in Mammals 146
6.5.1 DNA Methylation 146
6.5.2 Histone Modifications 148
6.5.3 Histone Variants in Meiotic Prophase I (Fig.6.5b) 153
6.5.3.1 The Specific Case of the XY Sex Body (Histone Modifications and Histone Variants) 153
6.5.3.2 H2A and H2B Variants 153
Phosphorylation of H2AX 153
Testis-Specific Histone Variants TH2A and TH2B 154
6.5.3.3 H3 Variants 154
6.5.3.4 H1 Variants 155
6.5.4 Noncoding RNAs During Spermatogenesis 155
6.6 How Could It Work: Are Meiotic Recombination Initiation Sites Defined by a Specific Combination of DNA Sequence and Chromatin Features? 156
6.6.1 Methylation of DNA Inhibits the Formation of Crossovers 156
6.6.2 Sequence Features and Open Chromatin at Recombination Initiation Sites 157
6.6.3 A Model: Chromatin Writers and Readers as Major Determinants of Meiotic Recombination 159
6.7 Perspectives 161
References 162
Chapter 7: Meiotic Pairing of Homologous Chromosomes and Silencing of Heterologous Regions 170
7.1 Introduction 171
7.2 Evolution of Sex Chromosomes 172
7.3 Homologous Chromosome Pairing in Meiotic Prophase 174
7.3.1 Bouquet Formation 174
7.3.2 Meiotic DNA Double-Strand Break Formation 174
7.3.3 Synaptonemal Complex Formation 175
7.3.4 Meiotic DNA Double-Strand Break Repair 176
7.3.5 Meiotic Checkpoint Regulation During Male Meiotic Prophase 177
7.4 Sex Chromosomal Behavior During Mammalian Spermatogenesis 178
7.4.1 Pairing of X and Y in Meiotic Prophase 178
7.4.2 Meiotic DSB Repair at X and Y 181
7.4.3 Meiotic Sex Chromosome Inactivation 182
7.4.4 Meiotic Silencing of Unsynapsed Chromatin 184
7.4.5 Postmeiotic Silencing of Sex Chromosomes 186
7.5 Silencing of X and Y During Spermatogenesis and X Chromosome Inactivation in Female Somatic Cells Are Independent Mechanism 187
7.6 Meiotic Silencing of Sex Chromosomes in a Species with Female Heterogamety 188
7.7 What Drives Meiotic Silencing in Mouse and Man? 189
7.8 Clinical Relevance of Meiotic Silencing 192
References 193
Chapter 8: Histone Variants during Gametogenesis and Early Development 200
8.1 Introduction 201
8.2 Meiotic Chromatin 205
8.2.1 Histone Variants 205
8.2.2 More Sex Chromosome Aspects 208
8.3 Spermiogenesis and Mature Sperm 209
8.4 Significance for Nucleosomes, Histone Variants for Embryonic Development 213
8.5 Male Transgenerational Inheritance and Effects 215
8.6 Future Directions 217
References 218
Chapter 9: Genome Organization by Vertebrate Sperm Nuclear Basic Proteins (SNBPs) 226
9.1 Packing the Paternal Genome with Small and Large Sperm-Specific Nuclear Basic Proteins 227
9.2 Packing Sperm Chromatin. The Roles of Acetylation and Phosphorylation 228
9.3 Mammalian Transition Proteins 232
9.4 Protamines. Packing Chromatin in an Orderly Fashion 235
9.5 Mammalian SNBPs and Infertility. The Intriguing Role of TPs and Protamines in DNA Integrity 236
9.6 Concluding Remarks 237
References 238
Chapter 10: Epigenetics in Male Reproduction: A Practical Introduction to the Informatics of Next Generation Sequencing 244
10.1 Introduction 245
10.1.1 Heritability, Disease, and Model Systems 247
10.2 Approaches and Online Resources for Epigenetic Investigation 248
10.2.1 DNA Methylation and Imprinting 248
10.2.2 Histone Substitution and Higher Order Chromatin Structure 249
10.2.3 Histone Modification 249
10.2.4 Transcriptional Modulation by Small RNAs 250
10.3 Deep Sequencing Approaches for Epigenetic Investigation 251
10.3.1 Scale of Sequencing Experiments 251
10.3.2 NGS Technologies Overview 252
10.3.3 Principles of NGS Sequencing 253
10.3.4 Illumina GAII and Roche 454 FLX 253
10.3.5 Applications of Deep Sequencing 255
10.3.6 Types of Sequencing 255
10.3.7 Sequencing Depth 256
10.3.8 Alignment Tools 258
10.3.9 Identification of Small RNAs 260
10.3.10 Sources of Error in Alignment and Interpretation 261
10.3.11 Peak Detection 262
10.3.12 Estimating False Discovery 264
10.3.13 Data Visualization 264
10.3.14 Sequencing Systems and Epigenetics 265
Suggested Reading and Environmental Epigenetic Effects 266
References 267
Part III: Re-organization of Nuclear Compartments During Gametogenesis 272
Chapter 11: Organization of Chromosomes During Spermatogenesis and in Mature Sperm 273
11.1 Introduction 274
11.2 Chromosome Organization in Somatic Interphase: Brief Outlook 274
11.3 From Spermatogonia to Early Spermatids 275
11.3.1 Proliferation 275
11.3.2 Stages of Meiosis I 276
11.3.2.1 Movements and Interactions of Telomeres and Centromeres During Prophase I of Meiosis 277
11.3.2.2 Proteins Participating in Telomere Movement 277
11.3.3 Sex Chromosomes 278
11.4 Spermiogenesis 279
11.5 Spermatozoa 279
11.6 Chromosome Positioning 281
11.7 Tripartite Organization of Human Sperm Chromatin 284
11.8 Concluding Remarks 285
References 286
Chapter 12: Nuclear Lamins in Mammalian Spermatogenesis 290
12.1 The Nuclear Lamina 290
12.2 Mammalian Germ Line-Specific Lamin Isoforms 292
12.3 Nuclear Lamins in Mammalian Meiosis 293
12.4 Nuclear Lamins in Mammalian Spermiogenesis 295
12.5 Nuclear Lamins in Spermatogenesis of Nonmammalian Vertebrates 297
12.6 Outlook 297
References 297
Part IV: Fundamental Aspects of Gene Expression Regulation During Gametogenesis 300
Chapter 13: Specific Transcription Regulatory Mechanisms of Male Germ Cells 301
13.1 Introduction 301
13.1.1 Transcriptional Regulation in Male Germ Cells of Drosophila Melanogaster 302
13.1.2 Genes Encoding Paralogs of Subunits of the TFIID Complex Are Essential for Normal Spermatogenesis in Mammals 306
13.1.2.1 TBP-Related Factors 306
13.1.2.2 Genes Encoding TAF Paralogs 308
13.1.3 CREM, ACT, and KIF17b Cooperate in an Integrated Regulatory Mechanism Required for Spermatogenesis in Mouse and Humans 311
13.2 What Have Mouse Knockout Studies Told Us About the Physiopathology of Human Infertility? 313
References 314
Chapter 14: The Chromatoid Body: A Specialized RNA Granule of Male Germ Cells 320
14.1 Introduction 320
14.1.1 RNA Processing in Male Germ Cells 321
14.1.2 A Highly Specialized RNA Granule 322
14.1.3 Unique Features of the CB 323
14.1.4 Components of the Chromatoid Body 324
14.1.5 The Critical Roles of MIWI and PIWI 325
14.1.6 Dynamic Movements of the CB 329
14.1.7 Regulation by Critical Interactions 330
14.1.8 RNA Granules in Somatic Versus Germ Cells 332
References 333
Chapter 15: Sperm RNA: Reading the Hidden Message 338
15.1 Introduction 339
15.2 Gene Expression Studies in Mature Spermatozoa: Historical Aspects 341
15.3 Gene Expression Studies in Mature Spermatozoa: In Relation to Sperm RNA Carriage 344
15.4 Sperm RNA as a Diagnostic Resource 347
15.5 Functions for Sperm RNA 350
15.6 Is the Spermatozoon Nucleus More Active Than We Think? 351
15.7 Conclusions 354
References 355
Glossary 363
Index 376