| Title page | 3 |
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| Copyright page | 4 |
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| PREFACE | 5 |
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| ABOUT THE EDITORS... | 8 |
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| ABOUT THE EDITORS... | 9 |
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| PARTICIPANTS | 10 |
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| Table of contents | 13 |
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| CHAPTER 1 EARLY EMBRYONIC CELL FATE DECISIONS IN THE MOUSE | 17 |
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| Abstract: | 17 |
| INTRODUCTION | 17 |
| LINEAGE ESTABLISHMENT AND THE PRE-STEM CELL PROGRAM:FORMATION OF THE BLASTOCYST | 18 |
| LINEAGE MAINTENANCE AND THE STEM CELL PROGRAM: BEYOND THE BLASTOCYST | 22 |
| THE SECOND LINEAGE DECISION: SUBDIVIDING THE ICM | 22 |
| CELL SIGNALING REGULATES PE/EPI SPECIFICATION | 23 |
| ESTABLISHMENT AND MODULATION OF PLURIPOTENCYIN THE EPI LINEAGE | 25 |
| CONCLUSION | 26 |
| REFERENCES | 27 |
| CHAPTER 2 NUCLEAR ARCHITECTURE IN STEM CELLS | 30 |
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| Abstract: | 30 |
| INTRODUCTION | 30 |
| FUNCTIONAL COMPARTMENTALIZATION OF THE ES CELL NUCLEUS | 31 |
| Organization of Chromosomes and Single Genes within the Nuclear Space | 31 |
| Lamina and the Nuclear Periphery | 33 |
| STEM CELL FEATURES OF OTHER NUCLEOPLASMIC SUBCOMPARTMENTS | 35 |
| Splicing Speckles and Cajal Bodies | 35 |
| Promyelocytic Leukemia Bodies | 35 |
| Polycomb Bodies | 36 |
| CHROMATIN FEATURES CHARACTERISTIC OF ES CELL NUCLEI | 36 |
| Hypermobility of Architectural Chromatin Proteins and Heterochromatin Formation | 36 |
| Hypertranscription and DNA Replication in ES Cells | 37 |
| Silencing Mechanisms at Developmental Regulator Genes | 38 |
| CONCLUSION | 38 |
| ACKNOWLEDGEMENTS | 38 |
| REFERENCES | 39 |
| CHAPTER 3 EPIGENETIC REGULATION OF PLURIPOTENCY | 42 |
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| Abstract: | 42 |
| INTRODUCTION | 42 |
| EPIGENETIC MODIFICATIONS | 44 |
| Modulators of Chromatin Structure and Dynamics | 45 |
| Histone Modifications | 45 |
| DNA Methylation | 46 |
| THE EPIGENOME OF ES CELLS | 47 |
| Chromatin Structure and Dynamics | 47 |
| Histone Modifications | 48 |
| DNA Methylation | 51 |
| CONCLUSION | 52 |
| ACKNOWLEDGEMENTS | 53 |
| REFERENCES | 53 |
| CHAPTER 4 AUTOSOMAL LYONIZATION OF REPLICATION DOMAINS DURING EARLYMAMMALIAN DEVELOPMENT | 57 |
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| Abstract: | 57 |
| INTRODUCTION | 58 |
| REPLICATION TIMING PROGRAM: AN ELUSIVE MEASURE OF GENOME ORGANIZATION | 58 |
| Early Experiments | 58 |
| The Lessons from X Chromosome Inactivation | 60 |
| Replication Timing Landscape on Autosomes | 61 |
| AN EVOLUTIONARILY CONSERVED EPIGENETIC FINGERPRINT | 64 |
| REPLICATION TIMING AS A QUANTITATIVE INDEX OF 3-DIMENSIONAL GENOME ORGANIZATION | 65 |
| REPLICATION TIMING REVEALS AN EPIGENETIC TRANSITION: AUTOSOMAL LYONIZATION AT THE EPIBLAST STAGE | 67 |
| REPLICATION TIMING AND CELLULAR REPROGRAMMING:FURTHER SUPPORT FOR AUTOSOMAL LYONIZATION | 68 |
| MAINTENANCE AND ALTERATION OF REPLICATION TIMING PROGRAM AND ITS POTENTIAL ROLES | 69 |
| CONCLUSION | 70 |
| ACKNOWLEDGEMENTS | 70 |
| REFERENCES | 71 |
| CHAPTER 5 PRESERVATION OF GENOMIC INTEGRITY IN MOUSE EMBRYONIC STEM CELLS | 75 |
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| Abstract | 75 |
| INTRODUCTION AND HISTORICAL PERSPECTIVE | 76 |
| MUTATION FREQUENCIES IN SOMATIC CELLS | 78 |
| The Frequency of Mutation Is Suppressed in Mouse ES Cells | 79 |
| ES Cell Populations Retain Pristine Genomes by Eliminating Cells with Damaged DNA | 82 |
| Mouse ES Cells Preferentially Utilize High-Fidelity Homology-Mediated Repair Rather Than Nonhomologous End-Joining to Repair Double Strand DNA Breaks | 86 |
| CONCLUSION | 88 |
| ACKNOWLEDGEMENTS | 89 |
| REFERENCES | 89 |
| CHAPTER 6 TRANSCRIPTIONAL REGULATION IN EMBRYONIC STEM CELLS | 92 |
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| Abstract: | 92 |
| INTRODUCTION | 92 |
| EMBRYONIC STEM CELLS AS A MODEL TO STUDY TRANSCRIPTIONAL REGULATION | 93 |
| TRANSCRIPTION FACTORS GOVERNING ESC PLURIPOTENCY | 94 |
| TRANSCRIPTIONAL REGULATORY NETWORK | 97 |
| TECHNOLOGIES FOR DISSECTING THE TRANSCRIPTIONAL REGULATORY NETWORK | 97 |
| THE CORE TRANSCRIPTIONAL REGULATORY NETWORK: Oct4, Sox2 AND Nanog | 98 |
| EXPANDED TRANSCRIPTIONAL REGULATORY NETWORK | 100 |
| ENHANCEOSOMES: TRANSCRIPTION FACTOR COMPLEX | 102 |
| INTEGRATION OF SIGNALING PATHWAYS TO TRANSCRIPTIONAL NETWORK | 103 |
| INTERFACE BETWEEN TRANSCRIPTIONAL AND EPIGENETIC REGULATION | 104 |
| CONCLUSION | 105 |
| ACKNOWLEDGEMENTS | 105 |
| REFERENCES | 105 |
| CHAPTER 7 ALTERNATIVE SPLICING IN STEM CELL SELF-RENEWAL AND DIFFERENTIATION | 108 |
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| Abstract: | 108 |
| INTRODUCTION | 108 |
| INTRODUCTION TO ALTERNATIVE SPLICING | 109 |
| ALTERNATIVE SPLICING OF GENES IMPLICATED IN STEMNESS AND DIFFERENTIATION | 109 |
| GENOME-WIDE METHODS TO IDENTIFY AND DETECT ALTERNATIVE SPLICING EVENTS | 114 |
| REGULATION OF ALTERNATIVE SPLICING BY RNA BINDING PROTEINS | 114 |
| CONCLUSION AND PERSPECTIVES | 117 |
| ACKNOWLEDGEMENTS | 118 |
| REFERENCES | 118 |
| CHAPTER 8 MicroRNA REGULATION OF EMBRYONIC STEM CELL SELF-RENEWAL AND DIFFERENTIATION | 121 |
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| Abstract: | 121 |
| INTRODUCTION: THE SELF-RENEWAL PROGRAM | 121 |
| EMBRYONIC STEM CELLS | 122 |
| miRNA BIOGENESIS AND FUNCTION | 122 |
| ESCC miRNAs PROMOTE SELF-RENEWAL | 124 |
| miRNAs INDUCED DURING ESC DIFFERENTIATION SUPPRESS THE SELF-RENEWAL PROGRAM | 126 |
| REGULATORY NETWORKS CONTROLLING miRNA EXPRESSION | 128 |
| miRNAs CAN PROMOTE OR INHIBIT DEDIFFERENTIATION TO IPS CELLS | 129 |
| miRNAs IN SOMATIC STEM CELLS | 129 |
| miRNAS IN CANCER CELLS | 130 |
| CONCLUSION | 130 |
| REFERENCES | <