By way of its clear and logical structure, as well as abundant high-resolution illustrations, this is a systematic survey of the players and pathways that control genome function in the mammalian cell nucleus. As such, this handbook and reference ties together recently gained knowledge from a variety of scientific disciplines and approaches, dissecting all major genomic events: replication, recombination, repair, and transcription. A major focus is on transcriptional control, including genome-wide interactions, chromatin remodeling, tissue-specific regulation, and epigenetics. With its focus on fundamental mechanisms and the associated biomolecules, this will remain essential reading for years to come.

Karsten Rippe leads the Research Group Genome Organization & Function at the German Cancer Research Center and the BioQuant Institute in Heidelberg, Germany. In his research, he combines molecular/cell biology and physics to quantitatively investigate and model the relation between nuclear DNA organization and cell function. Karsten Rippe has obtained his academic degrees from the University of
G?ttingen while working at the Max Planck Institute for Biophysical Chemistry and continued his scientific career at the University of Oregon in Eugene and the Kirchhoff-Institut f?r Physik in Heidelberg. He has authored more than 80 scientific publications in the fields of DNA structure, transcription and chromatin and has received several scientific awards, including the Otto Hahn medal of the Max Planck Society and the European Beckman DNA Award.

Preface xix

List of Contributors xxi

1 Deciphering DNA Sequence Information 1
Mark Kaganovich and Michael Snyder

1.1 Introduction 1

1.2 Genes and Transcribed Regions 1

1.3 Non-Coding Genomic Elements 4

1.4 Regulatory Information 10

1.5 Individual Genetic Polymorphisms and Their Effect on Gene Expression 16

1.6 Conclusion 16

2 DNA Methylation 21
Carina Frauer, Fabio Spada, and Heinrich Leonhardt

2.1 Introduction 21

2.2 Eukaryotic DNA Methyltransferases 24

2.3 Distribution of 5-Methylcytosine in the Mammalian Genome 27

2.4 Control of Gene Expression by DNA Methylation 31

2.5 DNA Demethylation 37

3 Nucleosomes as Control Elements for Accessing the Genome 55
Mekonnen Lemma Dechassa and Karolin Luger

3.1 Introduction and Basic Terminology 55

3.2 Nucleosomes are the Building Blocks of Chromatin 56

3.3 Nucleosomes Are Dynamic Macromolecular Assemblies 63

3.4 Histone Variants and Their Effect on Nucleosome Structure and Dynamics 66

3.5 Histone Modifications in Nucleosome and Chromatin Structure 68

3.6 DNA Sequence and Nucleosome Positioning 70

3.7 Histone Chaperones and Chromatin Dynamics 73

3.8 Outlook and Concluding Remarks 75

4 Histone Modifications and Their Role as Epigenetic Marks 89
Karl Nightingale

4.1 The Complexity of Histone Modifications 89

4.2 Regulating Histone Modifications in Chromatin 93

4.3 The “Histone Code” Hypothesis 95

4.4 Exploiting the Complexity of the Histone Code: “Crosstalk” Between Different Modifications 98

4.5 Are Histone Modifications Heritable Epigenetic Marks? 104

4.6 Conclusions 106

5 Chromatin Remodeling and Nucleosome Positioning 111
Gernot La¨ngst, Vladimir B. Teif, and Karsten Rippe

5.1 Introduction 111

5.2 Chromatin Remodeling Complexes 112

5.3 Mechanisms of Nucleosome Translocations 115

5.4 Positioning Nucleosomes in the Genome 118

5.5 Gene Regulation via Nucleosome Positioning 124

5.6 Conclusions 127

6 The Folding of the Nucleosome Chain 139
Karsten Rippe

6.1 Introduction 139

6.2 Experimental Systems 140

6.3 Nucleosome–Nucleosome Interactions 142

6.4 DNA Interactions with the Histone Octamer Protein Core 145

6.5 Architectural Chromosomal Proteins and Chromatin States 147

6.6 Chromatin Fiber Conformations 150

6.7 Conclusions 154

7 The Crowded Environment of the Genome 169
Ron Hancock

7.1 Introduction 169

7.2 Basics 169

7.3 Physicochemical Parameters of the Genome’s Environment 171

7.4 Implications of a Crowded Environment for the Conformation of the Interphase Genome 171

7.5 Assembly and Localization of Macromolecular Machines for Genome Transcription and Replication 175

7.6 The Environment of the Genome during Mitosis 177

7.7 Effects of a Crowded Environment on Searching for Targets in the Genome 178

7.8 The Relative Importance of Entropic and Ionic Interactions for the Conformations and Interactions of Macromolecules in the Nucleus 179

7.9 The Evolution of Genomes 180

8 The Nuclear Lamina as a Chromatin Organizer 185
Nikolaj Zuleger and Eric C. Schirmer

8.1 Introduction 185

8.2 Genome Organization with Respect to the Nuclear Periphery 187

8.3 Interactions between NE Proteins and Chromatin Proteins/Chromatin Regulatory Proteins 190

8.4 Mechanisms Directing Changes in Genome Organization during Development 193

8.5 Gene Regulation as a Consequence of Peripheral Positioning 198

8.6 Peripheral Chromatin Organization and Disease 201

8.7 Closing Remarks 203

9 Three-Dimensional Architecture of Genomes 211
Job Dekker

9.1 Introduction 211

9.3 Chromosome Architecture as Seen by 3C-Based Assays 218

9.4 3C-Based Data and Single Cell Observations 226

9.5 Towards an Integrated 3C-Based View of Genome Architecture 227

10 Transcriptional Initiation: Frequency, Bursting, and Transcription Factories 235
Kieran Finan and Peter R. Cook

10.1 Transcription in Mammalian Nuclei 235

10.2 Transcription Is an Infrequent Event 236

10.3 Transcription Is Noisy 238

10.4 What Causes “Bursting”? 245

10.5 Conclusion 250

11 Processing of mRNA and Quality Control 255
Ute Schmidt and Edouard Bertrand

11.1 Introduction 255

11.2 Biosynthesis of Messenger RNA 255

11.3 Nuclear Quality Control 265

11.4 Cytoplasmic Messenger RNA Quality Control: Nonsense-Mediated Decay, No-Go and Non-Stop Decay 268

11.5 Concluding Remarks 273

12 The Nucleolus 279
Saskia Hutten, Belinda J. Westman, Franc-ois-Michel Boisvert, Silvana van Koningsbruggen, and Angus I. Lamond

12.1 Introduction 279

12.2 The Nucleolus and Its DNA 280

12.3 The Nucleolus and RNPs: Temporary Visitors or Permanent Residents? 285

12.4 The Nucleolar Proteome 292

12.5 Concluding Remarks 295

13 Non-Coding RNAs as Regulators of Transcription and Genome Organization 309
Katalin Fejes To´th and Gregory Hannon

13.1 Introduction 309

13.2 Classification of Non-Coding RNAs 311

13.3 Small Regulatory RNAs and Their Diverse Nuclear Functions 314

13.4 ncRNAs in Dosage Compensation 324

13.5 Developmental Regulation of Hox Clusters by Cis- and Trans-Acting ncRNAs 328

13.6 Mechanisms of Transcriptional Regulation by Long ncRNAs 330

13.7 Conclusions 338

14 RNA Networks as Digital Control Circuits of Nuclear Functions 353
John S. Mattick

14.1 Introduction 353

14.2 The Information Content of the Genome 353

14.3 The Hidden Layer of Developmentally Expressed Non-Coding RNAs 354

14.4 RNA Control of Nuclear Functions 355

14.5 RNA as the Adaptor in Digital–Analog Transactions 356

14.6 RNA as the Substrate for Environment–Epigenome Interactions 357

14.7 Conclusion 358

15 DNA Replication and Inheritance of Epigenetic States 365
Armelle Corpet and Genevie`ve Almouzni

15.1 Replication in a Chromatin Context: Basic Issues and Principles 365

15.2 Duplication of Nucleosome Organization 368

15.3 Maintenance of Epigenetic Marks and Post-translational Modifications 375

15.4 Concluding Remarks 383

16 Interplay and Quality Control of DNA Damage Repair Mechanisms 395
Berina Eppink, Jeroen Essers and Roland Kanaar

16.1 Introduction 395

16.2 DNA Repair Pathways 396

16.3 Repairing DSBs 400

16.4 Repair during Replication 404

16.5 Interplay and Quality Control during DNA Damage Repair 409

16.6 Applications of Mechanistic Insight in DNA Repair in Anti-Cancer Treatment 410

17 Higher Order Chromatin Organization and Dynamics 417
Hilmar Strickfaden, Thomas Cremer, and Karsten Rippe

17.1 Introduction 417

17.2 Higher Order Chromatin Organization: From 10-nm Thick Nucleosome Chains to Chromosome Territories 418

17.3 Genome Accessibility 424

17.4 Mobility of Chromosomal Loci and Nuclear Bodies 426

17.5 Mitosis Causes Drastic Changes of Chromosome Territory Proximity Patterns in Cycling Cells 429

17.6 Large-Scale Chromatin Dynamics in Nuclei of Cycling and Post-Mitotic Cells 431

17.7 Considerations on Possible Mechanisms of Large-Scale Chromatin Dynamics 434

18 The Mitotic Chromosome: Structure and Mechanics 449
John F. Marko

18.1 Introduction 449

18.2 Structural Components of Mitotic Chromosomes 450

18.3 Large-Scale Organization of Mitotic Chromosomes 457

18.4 Mechanics of Mitotic Chromosomes 459

18.5 Molecular Connectivity of Mitotic Chromosomes 465

18.6 A Model for Mitotic Chromosome Structure and Function 468

18.7 Open Questions 474

19 Meiotic Chromosome Dynamics 487
Nancy Kleckner, Liangran Zhang, Beth Weiner, and Denise Zickler

19.1 Introduction 487

19.2 Recombination at the DNA Level 494

19.3 Coordination between Recombination and Chromosome Dynamics 500

19.4 Homologous Chromosome Pairing 507

19.5 Meiotic Recombination as a Paradigm for Spatial Patterning along Chromosomes 515

20 Understanding Genome Function: Quantitative Modeling of Chromatin Folding and Chromatin-Associated Processes 535
Mariliis Tark-Dame, Martijn S. Luijsterburg, Dieter W. Heermann and Roel van Driel

20.1 Modeling of Genome Functioning 535

20.2 Large-Scale Chromatin Folding 536

20.3 Assembly of Chromatin-Associated Multiprotein Complexes 543

20.4 Outlook 548

Index 557

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