Advances in Nuclear Architecture (eBook)

Foreword 6
Contents 8
Chapter 1: Nuclear Subdomains and Cancer 10
1.1 Introduction 13
1.2 Promyelocytic Leukemia Nuclear Bodies and Tumour Suppression 17
1.2.1 PML Plays a Role in Multiple Tumour Suppressor Pathways 19
1.2.1.1 The Regulation of p53 Function by PML: A Paradigm for PML NB Function in Tumour Suppression 19
1.2.1.2 PML NBs and the Response to Genotoxic Stress 23
1.2.1.3 PML Controls Cellular Fate by Mediating Apoptosis and Cellular Senescence 25
1.2.2 Pathways Regulating PML Protein Stability Represent Possible Therapeutic Targets for Cancer Treatment 29
1.2.2.1 Regulation of PML Protein Stability by Sumoylation 29
1.2.2.2 Regulation of PML Protein Stability by Phosphoryation 31
1.2.3 Summary of PML NBs and Cancer 32
1.3 The Nucleolus and Cancer 33
1.3.1 AgNOR Scores as a Prognostic Indicator in Cancer 35
1.3.2 Nucleolar Function, Ribosome Biogenesis and the Inter-Regulation of Cell Growth and Proliferation 36
1.3.3 Nucleolar Functions Beyond Ribosome Production 38
1.3.3.1 The Nucleolus, p53, ARF, and the Cell Stress Response 39
1.3.3.2 Nucleostemin 40
1.3.3.3 Nucleophosmin 41
1.3.3.4 Nucleolin 41
1.3.3.5 Other Tumour Suppressors 42
1.3.3.6 The Nucleolus and Genome Maintenance 42
1.3.4 Nucleolar Function as a Cancer Initiator 44
1.3.5 Summary of the Nucleolus and Cancer 45
1.4 The Perinucleolar Compartment in Cancer Cells 46
1.4.1 The PNC Formation is Associated with Malignant Phenotype In Vitro and In Vivo 47
1.4.2 Association of PNC with Pol III Transcription 48
1.4.3 The PNC is Nucleated upon DNA 49
1.5 Evidence for the Coordination of Function Between Nuclear Subdomains in Tumour Suppression 50
1.6 Concluding Remarks 53
References 53
Chapter 2: Spatial Point Process Analysis of Promyelocytic Leukemia Nuclear Bodies 68
2.1 Introduction 68
2.2 Spatial Point Processes: Theory, Models and Statistics 71
2.3 Spatial Point Process: Definitions and Calculations 71
2.4 Binomial and Poisson Point Processes 72
2.4.1 The Binomial Point Process 72
2.4.2 The Homogeneous Poisson Point Process 73
2.4.3 Inhomogeneous Poisson Point Process 74
2.4.4 Estimating Intensity 74
2.4.5 Edge-Effects 75
2.5 Testing for Spatial Point Processes 75
2.5.1 The Empty Space Function F 75
2.5.2 The Nearest Neighbour Distribution Function G 76
2.5.3 The Pair Correlation Function g 76
2.5.4 The K Function 77
2.5.5 Relationships Between Spatial Point Process Functions 77
2.6 More Complicated Point Process Models 78
2.6.1 Gauss–Poisson Process 79
2.6.2 Matérn Cluster Process 79
2.6.3 Markov Point Processes 80
2.6.4 Cox Processes 80
2.7 Marked Spatial Point Processes 81
2.8 Bivariate Spatial Point Process Analysis of PML NBsand RNA Polymerase II 82
2.9 A Marked Inhomogeneous Poisson Process Model for PML 84
2.10 Conclusion 90
Appendix 92
References 93
Chapter 3: Quantitative Approaches to Nuclear Architecture Analysis and Modelling 95
3.1 Introduction 96
3.2 Experimental Evidence for Nuclear Genome Large Scale Architecture 97
3.3 Quantitative Microscopy of Nuclear Genome Architecture 98
3.4 Quantitative Modeling of Nuclear Genome Large Scale Architecture 102
3.5 Application of the SCD Computer Model to Predict Cell Type Specific Radiation-Induced Chromosomal Aberrations 106
3.6 Extension of the SCD Model of Large Scale Nuclear Genome Architecture to Simulate Interactions with Other Nuclear Bodies 111
3.6.1 SCD model and banding pattern 113
3.6.2 Calibration 115
3.6.3 Comparison with Experimental Observations 117
3.7 The Dynamics of Large Scale Nuclear Genome Structure in the Human Cell Nucleus 118
3.8 Towards Quantitative Analysis of Nuclear Genome Nanostructure I: Computer Models 122
3.9 Towards Quantitative Analysis of Nuclear Genome Nanostructure II: Perspectives of Superresolution Light Microscopy 125
3.9.1 Perspectives 131
References 132
Chapter 4: Statistical Shape Theory and Registration Methods for Analyzing the 3D Architecture of Chromatin in Interphase Cell Nuclei 138
4.1 Introduction 139
4.2 Image Data and Computational Methods 141
4.2.1 Image Data 141
4.2.2 Uniformity Test 142
4.2.3 Triangulation 143
4.2.4 Point-Based Rigid Registration 143
4.2.5 Investigation of the Statistical Distribution Using Kendall’s Spherical Coordinates 144
4.2.6 Statistical Shape Modeling Using the Fisher Distribution 144
4.2.7 Quantitative Analysis of the Correlation Between the Shapes of the Active and Inactive X-Chromosomes 145
4.2.8 Spatial Normalization of Cell Nuclei Using Non-rigid Registration 145
4.3 Experimental Results 146
4.4 Discussion 151
References 152
Chapter 5: Nuclear Molecular Motors for Active, Directed Chromatin Movement in Interphase Nuclei 155
5.1 Molecular Motors 155
5.2 The Dynamic Nucleus 157
5.3 Acto: Myosin Molecular Motors in Nuclei 158
5.3.1 Nuclear Actin and Actin-Related Proteins 158
5.3.2 Nuclear Myosins 160
5.3.2.1 Nuclear Myosin 1b (NMIb) 161
5.3.2.2 Distribution of NM1b 162
5.4 Nuclear Motor Protein Involvement in Long Range Movement of Chromatin 164
5.4.1 Activated Gene Loci Movement in Real Time 165
5.4.2 Exogenous Plasmid Intranuclear Movements Use the Host Cells’ Nuclear Actin 166
5.4.3 Rapid Repositioning of Whole Chromosome Territories 167
5.4.4 Active Chromosomal Movement Towards a Specific Nuclear Entity 169
5.4.5 Long Range Chromatin Movement to the Nuclear Periphery in Yeast 170
5.5 Future Perspectives 171
References 173
Chapter 6: Methodology for Quantitative Analysis of 3-D Nuclear Architecture 179
6.1 Introduction 180
6.2 Segmentation of CLSM Image Data 181
6.3 Investigating Nuclear Architecture 185
6.3.1 Radial Analysis 186
6.3.2 Co-Localisation Analysis 186
6.3.3 Distance-Based Analysis 187
6.3.4 Spatial Point Pattern Analysis 187
6.4 The Future of Analysing Nuclear Architecture – Image Registration? 189
6.5 Conclusion 191
References 191
Chapter 7: Thinking Holistically About Gene Transcription 194
7.1 Introduction 194
7.2 The Nucleus 195
7.3 Transcription Factories 196
7.4 Gene Networks 197
7.5 Organization in the Chromatin Compartment 200
7.6 Global Nuclear Organization 202
7.7 Modelling Gene Expression 206
References 208
Index 211