Nuclear, Chromosomal, and Genomic Architecture in Biology and Medicine

Preface
Book Abstract
Contents
Part I: Genome Architecture, Evolution, and Cell Fate
Chapter 1: Networks and Islands of Genome Nano-architecture and Their Potential Relevance for Radiation Biology
1.1 Introduction to Radiation-Induced DNA Damage and Repair
1.2 Methods of Nanoscale Microscopic Analysis of the Cell Nucleus as a System at a Whole: Single-Molecule Localization Microsc...
1.3 The Cell Nucleus: A Complex System as a Whole
1.4 Radiation-Induced Chromatin Damage: A Complex System as a Whole Under Environmental Stress
1.5 Experimental Hints for System Response as a Whole After Radiation-Induced DNA Damaging
1.6 Experimental Hints for Similarity of Local System Response (Islands) After Radiation-Induced DNA Damaging
1.7 Conclusion
References
Chapter 2: A Unified Genomic Mechanism of Cell-Fate Change
2.1 Introduction: Self-Organization of Genome Expression
2.2 Classical Self-Organized Criticality Models
2.2.1 c-SOC Model
2.2.2 Rapid SOC Model
2.3 SOC Control of Genome Expression Regulation
2.4 Genome Engine: Open Thermodynamic View of Genome Expression System
2.5 Self-Organization of Whole Gene Expression Through Coordinated Chromatin Structural Transition
2.6 Synchronization Between Critical Point and Genome Attractor: CP as the Organizing Center of Cell-Fate Change
2.6.1 Critical Transition Transmitted to the Genome
2.7 Discussion
2.7.1 Different Biological Systems
2.7.1.1 MCF-7 Breast Cancer Cells: Global and Local Perturbations
2.7.1.2 HL-60 Human Leukemia Cells: Commitment to Differentiation
2.7.1.3 Human and Mouse Embryos: Developmental Oocyte-to-Embryo Transition
2.7.2 Genome Computing: CP Acting as the Center of Genome Computing
2.8 Conclusion: A Unified Genomic Mechanism
2.9 Methods
2.9.1 Biological Data Sets
2.9.2 Normalized Root Mean Square Fluctuation (nrmsf)
2.9.3 Updated Expression Flux Analysis
References
Chapter 3: Alterations to Genome Organisation in Stem Cells, Their Differentiation and Associated Diseases
3.1 Introduction
3.2 Different Types of Stem Cells
3.3 Nuclear Structures
3.3.1 The Nuclear Lamina
3.3.2 Nucleoli and Nuclear Bodies
3.4 Interphase Genome Organisation
3.5 Cellular Senescence
3.6 Alterations to Nuclear Organisation Leading to Plasticity in Differentiated Cells
3.7 Genome Behaviour in Laminopathies, Including Hutchinson-Gilford Progeria Syndrome
3.8 Chromosomal Translocations, Genome Reorganisation and Disease
3.9 Genome Behaviour in Colorectal Cancer, a Solid Tumour
3.9.1 GREM1 Duplication
3.10 Summary
References
Chapter 4: How Genomes Emerge, Function, and Evolve: Living Systems Emergence-Genotype-Phenotype-Multilism-Genome/Systems Ecol...
4.1 Introduction
4.2 A Short History of 3D Genome Organization and Its Finalization
4.2.1 The History of Genome Organization
4.2.2 Filling the Missing Gaps: Finalizing 3D Genome Organization and Dynamics
4.3 How Genomes Emerge, Function, and Evolve
4.3.1 Systems Consistency of the 3D Genome Organization
4.3.2 A Systems Statistical Genome Mechanics
4.4 Genotype-Phenotype Entanglement and Genome Ecology
4.4.1 Genotype-Phenotype Relation and Darwinian-Lamarckian Evolution
4.4.2 Phenomenological and Statistical Systems Mechanics/Thermodynamics of Genome Entanglement and Ecology
4.5 Revisiting Genome Evolution, Function, and Meta-Semantics
4.5.1 Approaching Holistic Genome Evolution from First Principles
4.5.2 Approaching a Meta-Semantics of Genome Function from First Principles
4.6 Fundamental Principles of Life: On Statistical Mechanics Trinity, Equilibria and Time
4.7 Conclusion
References
Chapter 5: Integrating Multimorbidity into a Whole-Body Understanding of Disease Using Spatial Genomics
5.1 Introduction
5.2 What Is Multimorbidity?
5.3 Why Is Multimorbidity Important?
5.4 Why Is a Whole-Body Understanding of Multimorbidity Important?
5.5 Methods to Explore Multimorbidity
5.6 What Is Spatial Genomics?
5.7 How Does Integrating Nuclear Structure Help to Understand MCC?
5.8 What Are the Limitations?
5.9 Future Perspectives
5.10 Conclusion
References
Part II: Chromosomes and Chromatin Architecture and Dynamics
Chapter 6: Mitotic Antipairing of Homologous Chromosomes
6.1 Introduction
6.1.1 Advantages of a Diploid (2n) Organism Derived from Maternal and Paternal Genomes and Chromosome Organization
6.1.2 Parental Genome Segregation in the Zygote
6.1.3 Radial Chromosome Organization
6.1.4 Significance of Homologous Chromosome Position/Distribution
6.1.5 Haploid Set-Based Segregation of Homologous Chromosomes
6.1.6 Intranuclear Location of Individual Chromosomes Varies
6.1.7 Visualization of Individual Homologous Chromosomes
6.1.8 Definition of Homologous Chromosome Pairing/Antipairing
6.1.9 Mechanisms Underlying Haploid Set-Based Segregation
6.1.10 Tetraploidy
6.1.11 Loss of Antipairing in Tumorigenesis/Cancer
6.1.12 Mitotic Chiasmata/Quadriradial Configuration and Recombination
6.1.13 Mitotic Chiasmata and Crossing Over
6.1.14 Mitotic Recombination and Loss of Heterozygosity (LOH)
6.1.15 Mitotic Recombination/LOH and Impact of Disease (Molecular Self-Correction)
References
Chapter 7: CENP-A: A Histone H3 Variant with Key Roles in Centromere Architecture in Healthy and Diseased States
7.1 Introduction
7.2 Coevolution of Centromere DNA, CENP-A, and HJURP
7.2.1 Diversity of Centromere DNA and CENP-A
7.2.2 Centromere Drive
7.2.3 Coevolution of HJURP and CENP-A
7.3 Building the Centromere Foundation on DNA
7.3.1 Characterizing the Human Centromere Before Long-Read Sequencing
7.3.2 New Insights from Telomere-to-Telomere Sequencing
7.3.3 Impact of Centromere DNA on Centromere Function
7.3.3.1 CENP-B Binding
7.3.3.2 Centromere Transcription
7.3.3.3 Nucleosome Phasing and Cruciform Formation
7.3.3.4 Pericentromere Heterochromatin
7.4 Deposition and Maintenance of CENP-A at the Centromere
7.4.1 Licensing Centromere Chromatin During Kinetochore Assembly
7.4.2 Loading of New CENP-A in Early G1
7.4.3 Recycling CENP-A at the Replicating Centromere
7.5 CENP-A Regulation from Healthy to Diseased States
7.5.1 Transcriptional Regulation of CENP-A
7.5.2 Potential Role for CENP-A in Stem Cell Differentiation
7.5.3 CENP-A Misregulation in Cancer
7.5.4 Impact of p53 Status on CENP-A Overexpression in Cancer
7.5.5 Centromere Nuclear Positioning in Healthy Tissues and Cancer
7.6 Conclusions
References
Chapter 8: Scaling Relationship in Chromatin as a Polymer
8.1 Chromatin and Polymer Physics
8.2 Scaling Law: Universal Rules Behind the Diverse Behaviors of Polymers
8.3 Scaling Relationship in Base-Pair Length vs. Three-Dimensional Distance
8.4 Scaling Relationship of Chromatin in the Nucleus Revealed by Hi-C Analysis
8.5 Scaling Relationship in Time vs. Travel Distance
8.5.1 Brownian Motion of a Particle
8.5.2 Particles in a Polymer: Rouse Model
8.5.3 Hydrodynamic Interaction: Zimm Model
8.5.4 The Mesh Size: Screening of Hydrodynamic Interaction in Polymer Solution
8.6 Experimental Characterizations of MSD-τ Relationship for Chromatin in the Cell
8.6.1 Chromatin Mobility Has Been Characterized for Different Time Scales
8.6.2 Chromatin Mobility Changes During Embryogenesis in the Nematode Caenorhabditis elegans
8.7 Perspectives
References
Chapter 9: Chromatin Dynamics During Entry to Quiescence and Compromised Functionality in Cancer Cells
9.1 Introduction
9.2 Gene Expression Changes During Quiescence Entry
9.2.1 Core Quiescence Program
9.2.2 The DREAM Complex
9.2.3 Epigenetic Status in Quiescence
9.2.4 Other Post-transcriptional Controls
9.3 Nuclear Reorganisation and Chromosome Positioning
9.3.1 The Role of Microtubules During Quiescence Entry
9.3.2 The Role of Nuclear Myosin During Quiescence Entry
9.4 Chromatin Condensation During Quiescence Entry
9.4.1 The Condensin Complex
9.4.2 The Role of the Condensin Complex in Quiescence
9.4.3 H4K20 Methylation and Condensation
9.5 Quiescence and Disease
9.6 Concluding Remarks
References
Chapter 10: Functional Aspects of Sperm Chromatin Organization
10.1 Introduction
10.2 Sperm Chromatin Structure
10.2.1 Somatic Chromatin
10.2.2 Sperm Chromatin
10.2.2.1 Condensing the DNA Through Protamines
10.2.2.2 Protamine-DNA Toroids
10.2.2.3 Sperm DNA Loop Domains
10.2.2.4 Tertiary Structures of Sperm Chromatin
10.3 The Toroid-Loop Model for Sperm Chromatin Structure
10.3.1 Aspects of the Model That Are Supported by Experimental Evidence
10.3.2 Aspects of the Model That Are Proposed for Which Direct Experimental Data Is Yet to Be Acquired
10.4 Functional Aspects of Sperm Chromatin Structure: Sperm Chromatin Retains Some Active Properties
10.4.1 DNA Replication of the Sperm Chromatin
10.4.2 Sperm Chromatin Fragmentation
10.5 The Impact of Sperm Organization to Human Infertility
10.6 Conclusions
References
Part III: Mechanosensitive and Epigenetic Regulators of Gene Expression and Chromatin Organization
Chapter 11: The LINC Complex Assists the Nuclear Import of Mechanosensitive Transcriptional Regulators
11.1 Introduction
11.2 Scaffolds for Signal Transmission Across the Nuclear Envelope
11.2.1 The NPC
11.2.2 The LINC Complex
11.2.3 Association of the NPC with the Cytoskeleton and Nucleoskeleton
11.3 LINC Complex-Assisted Nuclear Translocation of Mechanosensitive Transcription Factors
11.3.1 Nucleocytoplasmic Trafficking of β-Catenin
11.3.2 Nucleocytoplasmic Trafficking of YAP and TAZ
11.4 Concluding Remarks
References
Chapter 12: Epigenetic-Mediated Regulation of Gene Expression for Biological Control and Cancer: Cell and Tissue Structure, Fu...
12.1 An Epigenetic Perspective of Biological Control and Pathology
12.2 The Human Epigenome Is Organized in Hierarchical Yet Interdependent Levels
12.3 Epigenetic Modifications Establishing Lineage Specification Are Crucial Points of Alterations During Tumorigenesis
12.3.1 DNA Methylation in Normal Cells and Dysregulation in the Cancer-Compromised Genome
12.3.2 Crosstalk Between DNA Methylation and Posttranslational Histone Modifications
12.3.3 Alterations in Histone Modification Enzymes in Cancer
12.4 Chromatin Structures Including Chromatin Fibers, Topologically Associating Domains, and Compartments and Histone Modifica...
12.4.1 How the Chromatin Fiber Folds into Higher-Order Structures
12.4.2 Higher-Order Chromatin Structures, TADs, and Compartments
12.5 Subnuclear Trafficking and Phase Separation- Mechanisms That Contribute to the Subnuclear Organization Assembly and Activ...
12.6 Super-Enhancers in Cancer
12.7 Alteration of the Nuclear Organization as a Hallmark of Cancer
12.8 Conclusion
References
Chapter 13: Epigenetic-Mediated Regulation of Gene Expression for Biological Control and Cancer: Fidelity of Mechanisms Govern...
13.1 An Epigenetic Perspective of Cell Cycle Control
13.2 Interplay Between Cell Cycle Progression, Cellular Transcriptional Machinery, and Epigenetics
13.2.1 Epigenetic Control During Mitosis
13.3 Mechanisms of Chromosome Behavior During Mitosis
13.4 Condensin-Mediated Remodeling of Mitotic Chromosomes
13.5 Chromatin Decondensation Upon the Mitotic Exit
13.6 Involvement of TADs and CTCF in Chromatin Structure Reconfiguration After Mitosis
13.7 Mitotic Gene Bookmarking: An Epigenetic Program for Cell Identity
13.7.1 Role of the Histone Posttranslational Modifications (PTMs)
13.7.2 Transcription Factors (TFs), Key Regulators of Memory Program for Resetting Transcription
13.7.3 Nucleosome Repositioning, an Alternative Bookmarking Mechanism
13.7.4 Mitotic Transmission of Phenotype-Specific mRNAs in Cancer Cells
13.8 Perturbation of Chromosomal Rearrangements in Cancer
13.9 Transcription Factor Fusion Proteins as Therapeutic Targets
13.10 Conclusion
References
Chapter 14: Histone Modifications in Mouse Pronuclei and Consequences for Embryo Development
14.1 Introduction
14.2 Remodeling of Female and Male Chromatins During the First Cell Cycle
14.2.1 Gametes
14.2.2 Female and Male Chromatin in the Zygotic Cell Cycle
14.3 Demethylation of Paternal and Maternal DNA
14.4 Core Histones Variants
14.4.1 Histone H2A Variants
14.4.2 Histone H3 Variants
14.5 Modifications of Core Histones Tails
14.5.1 Acetylation of Lysine Residues
14.5.2 Phosphorylation of Histone H3
14.5.3 Histone Methylation
14.6 Conclusions
References
Part IV: Nucleus, Nucleolus, and Nucleolar Organizer Architecture
Chapter 15: Nuclear Architecture in the Nervous System
15.1 Introduction
15.2 Nuclear Geometry
15.3 Nuclear Bodies
15.4 Heterochromatin Compartment
15.5 Radial Positioning
15.6 Chromatin Condensation/Decondensation
15.7 Chromatin Interaction/Loops Between Genes and Cis-Regulatory Elements (CREs)
15.8 Conclusion and Future Direction
References
Chapter 16: Nuclear Morphological Abnormalities in Cancer: A Search for Unifying Mechanisms
16.1 Introduction
16.2 Regulation of Nuclear Size
16.3 Perturbations to the Nuclear Lamins in Cancers
16.4 Implications of Nuclear Lamin Alterations for Nuclear Morphology
16.5 Chromatin Regulators and Nuclear Morphology in Cancer
16.6 Nuclear Membrane Proteins
16.7 Cytoskeletal Forces
16.8 Conclusions
References
Untitled
Chapter 17: Nuclear Organization in Response to Stress: A Special Focus on Nucleoli
17.1 Introduction
17.2 General Organization of the Nucleus
17.2.1 Nuclear Lamina and Chromatin
17.2.2 Membraneless Bodies of the Nucleus
17.2.2.1 Nucleolus
17.2.2.2 Nuclear Speckles
17.2.2.3 Paraspeckles
17.2.2.4 Cajal Bodies
17.2.2.5 PML Bodies
17.3 Nuclear-Targeting Stress Types and their Effects
17.3.1 DNA Damage
17.3.2 Transcriptional Inhibition and RNA Processing-Related Damage
17.3.3 Proteotoxic Stress
17.4 The Nucleolus as a Central Hub for Nuclear Stress Sensing
17.4.1 Criteria of Nucleolar Stress
17.4.2 Nucleolar Changes in Response to RNA Polymerase Inhibitors and DNA Damaging Agents
17.4.3 Nucleolus in Response to Proteotoxic Stress
17.4.4 Nucleolus in Response to Viral Stress
17.5 Concluding Remarks
References
Chapter 18: Simulation of Different Three-Dimensional Models of Whole Interphase Nuclei Compared to Experiments - A Consistent...
18.1 Introduction
18.2 Theory
18.2.1 Simulation Methods
18.2.1.1 Chain Properties
18.2.1.2 Metaphase Starting Configurations and Simulated Annealing
18.2.1.3 Brownian Dynamics Algorithm and Decondensation from Metaphase into Interphase
18.2.1.4 Parallelization of Simulation Code
18.2.2 Simulated Models and their Properties
18.2.2.1 Multi-Loop-Subcompartment (MLS) Model
18.2.2.2 Random-Walk/Giant-Loop (RW/GL) Model
18.2.2.3 Excluded Volume and Nuclear Volume Properties Used
18.3 Results and Discussions
18.3.1 Morphology and General Properties of Simulated Nuclei
18.3.1.1 Rendering and Simulation of EM and CLSM Images
18.3.1.2 Morphology of Simulated Nuclei
18.3.1.3 Radial Mass and Density Distribution of Simulated Nuclei
18.3.1.4 Intensity and Mass Distribution in CLSM-Stacks of Simulated Nuclei
18.3.2 Properties of Simulated Chromosome Territories
18.3.2.1 Radial Mass and Density Distribution of Simulated Chromosome Territories
18.3.2.2 Roundness of Simulated Chromosome Territories
18.3.2.3 Spatial Distance between Arbitrary and Nearest Chromosome Territories
18.3.2.4 ``Volume´´ and Overlap of Simulated Chromosome Territories Based on CLSM Images
18.3.3 Properties of MLS Subchromosomal Domains
18.3.3.1 Radial Mass Distribution of Subchromosomal Domains
18.3.3.2 Spatial Distance between Genetically Adjacent Subchromosomal Domains
18.3.3.3 Spatial Distance between Spatially Arbitrary and Nearest Subchromosomal Domains
18.3.3.4 ``Volume´´ and Overlap of Subchromosomal Domains Based on CLSM Images
18.3.4 Position Independent Spatial Distances between Genomic Markers
18.4 Conclusion
References
Chapter 19: Nucleolar Organizer Regions as Transcription-Based Scaffolds of Nucleolar Structure and Function
19.1 Introduction
19.2 NOR Function and Nucleolar Organization
19.2.1 The Composition and Function of NORs
19.2.2 Nucleolar Structure Is Built around the Transcription of NOR Sequences
19.2.3 Cellular Mechanisms to Regulate NOR Transcription
19.2.4 NOR Activity as a Determinant of Nuclear Position
19.2.5 Consequences of Co-Location of NORs within a Nucleolus
19.2.6 Nucleolar Maintenance by DNA Organizers and Biophysical Principles under Stress
19.3 Techniques for Analyzing NOR Function and Nucleolar Organization
19.3.1 Visualization of the NOR Arrays
19.3.2 Analysis of rDNA Array Sequence Variation
19.3.3 Methods for Quantifying rDNA Transcriptional Activity
19.3.4 Techniques to Study Dynamic rDNA Organization
19.4 NOR and Nucleolar Organization in Disease & Medicine
19.4.1 Alterations in NOR Structure
19.4.2 Increased NOR Activity and Altered Nucleolar Morphology in Cancer
19.4.3 Changes in NOR Activity and Nucleolar Morphology Associated with Aging and Longevity
19.4.4 Decreased NOR Activity in Ribosomopathies and Neurodegenerative Diseases
19.5 Concluding Remarks
References
Chapter 20: A Transient Mystery: Nucleolar Channel Systems
20.1 Background
20.2 Nucleolar Channel Systems: Structure and Function
20.3 NCS Relationship with the Nuclear Pore Complex
20.4 NCS in Reproductive Physiology
20.5 Applying New Imaging Platforms/Techniques to Study Nucleolar Channel Systems
20.6 Future Directions
References
Part V: Nuclear Actin Role in Polarization, Genome Organization, and Gene Expression
Chapter 21: Cellular Polarity Transmission to the Nucleus
21.1 Introduction
21.2 Evidence of Nuclear Polarity along the Apico-Basal (Planar) Axis
21.3 Transmission of Cellular Front-Rear Polarity to the Nucleus
21.4 Potential Involvement of Nuclear Polarity in Physiological and Pathological Conditions
21.5 Outlook
References
Chapter 22: The Role of Nuclear Actin in Genome Organization and Gene Expression Regulation During Differentiation
22.1 Introduction
22.2 Nuclear Actin in Chromatin Regulation and 3D Genome Organization
22.3 The Nuclear Actin Pool in Transcriptional Reprograming During Differentiation
22.4 Interaction Between Nuclear Actin and Long Noncoding RNAs: A Future Research Direction
22.5 Concluding Remarks
References
Chapter 23: Nuclear Actin Dynamics in Gene Expression, DNA Repair, and Cancer
23.1 Introduction
23.1.1 Actin Dynamics in the Cytoplasm
23.1.2 Actin Visualization
23.1.3 Nuclear Actin Dynamics
23.2 Nuclear Actin and Chromosome Architecture
23.2.1 The Hierarchy of Chromosome Architecture
23.2.2 Organizing Chromosome Architecture by Nuclear Actin
23.2.3 Chromosome Architecture and Cancers
23.3 Nuclear Actin and Chromatin Remodeling
23.3.1 Nuclear Actin in the Chromatin Remodeling Complexes
23.3.2 Nuclear Actin and cBAF Complex
23.3.3 BAF Family and Cancers
23.3.4 Nuclear Actin and INO80 Complex
23.3.5 INO80 Family and Cancers
23.4 Nuclear Actin and Transcription Machinery
23.4.1 Nuclear Actin and MRTFs
23.4.2 Nuclear Actin and RNA Polymerases
23.4.3 Nuclear Actin and Pre-mRNA Splicing
23.4.4 Other Mechanisms
23.5 Nuclear Actin and DNA Repair
23.5.1 DSB Repair
23.5.2 Nuclear Actin-Mediated Repair of DSBs
23.6 Concluding Remarks
References