Genome Organization And Function In The Cell Nucleus E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1248

Veröffentlichungsjahr: 2012

Beschreibung

By way of its clear and logical structure, as well as abundant highresolution 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: transcription, replication, repair, recombination and chromosome segregation. A special emphasis is put on transcriptional control, including genome-wide interactions and non-coding RNAs, chromatin structure, epigenetics and nuclear organization. With its focus on fundamental mechanisms and the associated biomolecules, this will remain essential reading for years to come.

Leseprobe

Contents

Preface

List of Contributors

Chapter 1: Deciphering DNA Sequence Information

1.1 Introduction

1.2 Genes and Transcribed Regions

1.3 Non-Coding Genomic Elements

1.4 Regulatory Information

1.5 Individual Genetic Polymorphisms and Their Effect on Gene Expression

1.6 Conclusion

Acknowledgments

Chapter 2: DNA Methylation

2.1 Introduction

2.2 Eukaryotic DNA Methyltransferases

2.3 Distribution of 5-Methylcytosine in the Mammalian Genome

2.4 Control of Gene Expression by DNA Methylation

2.5 DNA Demethylation

Chapter 3: Nucleosomes as Control Elements for Accessing the Genome

3.1 Introduction and Basic Terminology

3.2 Nucleosomes are the Building Blocks of Chromatin

3.3 Nucleosomes Are Dynamic Macromolecular Assemblies

3.4 Histone Variants and Their Effect on Nucleosome Structure and Dynamics

3.5 Histone Modifications in Nucleosome and Chromatin Structure

3.6 DNA Sequence and Nucleosome Positioning

3.7 Histone Chaperones and Chromatin Dynamics

3.8 Outlook and Concluding Remarks

Chapter 4: Histone Modifications and Their Role as Epigenetic Marks

4.1 The Complexity of Histone Modifications

4.2 Regulating Histone Modifications in Chromatin

4.3 The “Histone Code” Hypothesis

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

4.5 Are Histone Modifications Heritable Epigenetic Marks?

4.6 Conclusions

Chapter 5: Chromatin Remodeling and Nucleosome Positioning

5.1 Introduction

5.2 Chromatin Remodeling Complexes

5.3 Mechanisms of Nucleosome Translocations

5.4 Positioning Nucleosomes in the Genome

5.5 Gene Regulation via Nucleosome Positioning

5.6 Conclusions

Acknowledgments

Chapter 6: The Folding of the Nucleosome Chain

6.1 Introduction

6.2 Experimental Systems

6.3 Nucleosome–Nucleosome Interactions

6.4 DNA Interactions with the Histone Octamer Protein Core

6.5 Architectural Chromosomal Proteins and Chromatin States

6.6 Chromatin Fiber Conformations

6.7 Conclusions

Acknowledgments

Chapter 7: The Crowded Environment of the Genome

7.1 Introduction

7.2 Basics

7.3 Physicochemical Parameters of the Genome’s Environment

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

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

7.6 The Environment of the Genome during Mitosis

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

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

7.9 The Evolution of Genomes

Chapter 8: The Nuclear Lamina as a Chromatin Organizer

8.1 Introduction

8.2 Genome Organization with Respect to the Nuclear Periphery

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

8.4 Mechanisms Directing Changes in Genome Organization during Development

8.5 Gene Regulation as a Consequence of Peripheral Positioning

8.6 Peripheral Chromatin Organization and Disease

8.7 Closing Remarks

Chapter 9: Three-Dimensional Architecture of Genomes

9.1 Introduction

9.2 3C-Based Methods to Study Chromosome Architecture

9.3 Chromosome Architecture as Seen by 3C-Based Assays

9.4 3C-Based Data and Single Cell Observations

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

Chapter 10: Transcriptional Initiation: Frequency, Bursting, and Transcription Factories

10.1 Transcription in Mammalian Nuclei

10.2 Transcription Is an Infrequent Event

10.3 Transcription Is Noisy

10.4 What Causes “Bursting”?

10.5 Conclusion

Acknowledgments

Chapter 11: Processing of mRNA and Quality Control

11.1 Introduction

11.2 Biosynthesis of Messenger RNA

11.3 Nuclear Quality Control

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

11.5 Concluding Remarks

Chapter 12: The Nucleolus

12.1 Introduction

12.2 The Nucleolus and Its DNA

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

12.4 The Nucleolar Proteome

12.5 Concluding Remarks

Acknowledgments

Chapter 13: Non-Coding RNAs as Regulators of Transcription and Genome Organization

13.1 Introduction

13.2 Classification of Non-Coding RNAs

13.3 Small Regulatory RNAs and Their Diverse Nuclear Functions

13.4 ncRNAs in Dosage Compensation

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

13.6 Mechanisms of Transcriptional Regulation by Long ncRNAs

13.7 Conclusions

Chapter 14: RNA Networks as Digital Control Circuits of Nuclear Functions

14.1 Introduction

14.2 The Information Content of the Genome

14.3 The Hidden Layer of Developmentally Expressed Non-Coding RNAs

14.4 RNA Control of Nuclear Functions

14.5 RNA as the Adaptor in Digital–Analog Transactions

14.6 RNA as the Substrate for Environment–Epigenome Interactions

14.7 Conclusion

Acknowledgments

Chapter 15: DNA Replication and Inheritance of Epigenetic States

15.1 Replication in a Chromatin Context: Basic Issues and Principles

15.2 Duplication of Nucleosome Organization

15.3 Maintenance of Epigenetic Marks and Post-translational Modifications

15.4 Concluding Remarks

Acknowledgments

Chapter 16: Interplay and Quality Control of DNA Damage Repair Mechanisms

16.1 Introduction

16.2 DNA Repair Pathways

16.3 Repairing DSBs

16.4 Repair during Replication

16.5 Interplay and Quality Control during DNA Damage Repair

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

Chapter 17: Higher Order Chromatin Organization and Dynamics

17.1 Introduction

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

17.3 Genome Accessibility

17.4 Mobility of Chromosomal Loci and Nuclear Bodies

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

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

17.7 Considerations on Possible Mechanisms of Large-Scale Chromatin Dynamics

Acknowledgment

Chapter 18: The Mitotic Chromosome: Structure and Mechanics

18.1 Introduction

18.2 Structural Components of Mitotic Chromosomes

18.3 Large-Scale Organization of Mitotic Chromosomes

18.4 Mechanics of Mitotic Chromosomes

18.5 Molecular Connectivity of Mitotic Chromosomes

18.6 A Model for Mitotic Chromosome Structure and Function

18.7 Open Questions

Acknowledgments

Chapter 19: Meiotic Chromosome Dynamics

19.1 Introduction

19.2 Recombination at the DNA Level

19.3 Coordination between Recombination and Chromosome Dynamics

19.4 Homologous Chromosome Pairing

19.5 Meiotic Recombination as a Paradigm for Spatial Patterning along Chromosomes

Acknowledgments

Chapter 20: Understanding Genome Function: Quantitative Modeling of Chromatin Folding and Chromatin-Associated Processes

20.1 Modeling of Genome Functioning

20.2 Large-Scale Chromatin Folding

20.3 Assembly of Chromatin-Associated Multiprotein Complexes

20.4 Outlook

Acknowledgments

Index

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The Editor

Karsten Rippe

Deutsches Krebsforschungszentrum (DKFZ) & BioQuant

Research Group Genome Organization & Function

Im Neuenheimer Feld 280

69120 Heidelberg

Germany

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For Mieko

Preface

The activities associated with the genome center around the readout, processing, maintenance and transfer of the information encoded in the DNA sequence. In eukaryotes, the corresponding processes like gene expression and RNA processing, as well as DNA repair, replication, recombination and genome segregation take place in the environment of the nucleus. It provides a complex dynamic organization that serves to establish two apparently contradicting functions: On the one hand the genome has to be protected from uncontrolled modifications that would compromise its function, and it has to be reliably replicated and segregated during cell division and meiosis. On the other hand it has to be remarkably plastic to allow for a dynamic (re)organization so that the cell is able to adopt different functional states.

To understand how this is accomplished, findings from research in genomics, chromatin, epigenetics and nuclear organization have to be integrated. This need is addressed in the present book by combining complementary and interconnected contributions from renowned experts in these different fields of research. Issues that are directly related to DNA sequence and epigenetic information are discussed in Chapters 1, 2, 4 and 15. Chromatin organization and dynamics are covered from the scale of a single nucleosome to that of whole chromosomes in Chapters 2–6, 8, 9, 15, 17–20. The architecture of the nucleus and its subcompartments are discussed in relation to genome function in Chapters 7–10, 12 and 17. Within this framework, the central genome activities are treated in dedicated chapters for transcription, RNA processing and non-coding RNAs (Chapters 10–14), DNA replication and repair (Chapters 15, 16) as well as genome segregation and recombination during cell division and meiosis (Chapters 18, 19). Finally, using two exemplary cases, protein complex assembly during DNA repair and chromatin folding, it is discussed how quantitative models are applied to describe and predict functional genome features (Chapter 20).

Bringing together results from these different research areas in one book has been a highly rewarding experience for me. It has provided me with new insight on how the genome structure and its nuclear environment are interconnected with its functions, and hopefully the readers of the book will share this view. I am most grateful to all authors for their excellent contributions, and I wish to thank my colleagues from the DKFZ and BioQuant, the members of my laboratory and the editorial staff from Wiley-VCH for their advice and help in preparing this book.

Heidelberg, July 2011

Karsten Rippe

List of Contributors

Geneviève Almouzni

Institut Curie

Research Center

UMR218 CNRS

26 rue d’Ulm

75248 Paris cedex 05

France

Edouard Bertrand

Institut de Génétique Moléculaire de

Montpellier

CNRS UMR 5535

1919, route de Mende

34293 Montpellier Cedex 5

France

François-Michel Boisvert

Wellcome Trust Centre for Gene

Regulation and Expression, College of Life Sciences

University of Dundee

Dundee DD1 5EH

United Kingdom

Peter R. Cook

University of Oxford

Sir William Dunn School of Pathology

South Parks Road

Oxford OX1 3RE

United Kingdom

Armelle Corpet

Institut Curie

Research Center

UMR218 CNRS

26 rue d’Ulm

75248

Paris cedex 05

France

Thomas Cremer

LMU Biozentrum

Department Biology II (Anthropology and Human Genetics)

Grosshadernerstrasse 2

82152

Planegg-Martinsried

Germany

and

Munich Center for Integrated

Protein Science Munich

81377 Munich

Germany

Mekonnen Lemma Dechassa

Howard Hughes Medical Institute and Colorado State University

Department of Biochemistry and Molecular Biology

Fort Collins

CO 80523-1870

USA

Job Dekker

University of Massachusetts Medical School

Program in Gene Function and Expression

Program in Systems Biology

Department of Biochemistry and Molecular Pharmacology

364 Plantation Street

Worcester

MA 01605

USA

Berina Eppink

Erasmus Medical Center

Department of Cell Biology and Genetics

3000 DR Rotterdam

The Netherlands

Jeroen Essers

Erasmus Medical Center

Department of Cell Biology and Genetics

3000 DR Rotterdam

The Netherlands

Katalin Fejes Tóth

California Institute of Technology

1200 E California Blvd, MC 156-29

Pasadena, CA 91125

USA

Kieran Finan

University of Oxford

Sir William Dunn School of Pathology

South Parks Road

Oxford OX1 3RE

United Kingdom

Carina Frauer

Center for Integrated Protein Science

Ludwig Maximilians University Munich

Department of Biology

82152 Planegg-Martinsried

Germany

Ron Hancock

Université Laval

Département de Médecine Moléculaire et Centre de Recherche en Cancérologie

9 rue MacMahon

Québec G1R2J6

Canada

Gregory Hannon

Howard Hughes Medical Institute,

Cold Spring Harbor Laboratory

Watson School of Biological Sciences

1 Bungtown Road

Cold Spring Harbor

NY 11724

USA

Dieter W. Heermann

University of Heidelberg

Institute for Theoretical Physics

Philosophenweg 19

69120 Heidelberg

Germany

and

The Jackson Laboratory

Bar Harbor

ME 04609

USA

Saskia Hutten

Wellcome Trust Centre for Gene

Regulation and Expression, College of Life Sciences

University of Dundee

Dundee DD1 5EH

United Kingdom

Mark Kaganovich

Stanford University School of Medicine

Department of Genetics

Stanford, CA 94305

USA

Roland Kanaar

Erasmus Medical Center

Department of Cell Biology and Genetics

3000 DR Rotterdam

The Netherlands

and

Erasmus Medical Center

Department of Radiation Oncology

3000 DR Rotterdam

The Netherlands

Nancy Kleckner

Harvard University

Department of Molecular and Cellular Biology

Cambridge, MA 02138

USA

Angus I. Lamond

Wellcome Trust Centre for Gene

Regulation and Expression, College of Life Sciences

University of Dundee

Dundee DD1 5EH

United Kingdom

Heinrich Leonhardt

Center for Integrated Protein Science Ludwig Maximilians University Munich

Department of Biology

82152 Planegg-Martinsried

Germany

Gernot Längst

Universität Regensburg

Biochemie III

Universitätsstrasse 31

93053 Regensburg

Germany

Karolin Luger

Howard Hughes Medical Institute and Colorado State University

Department of Biochemistry and Molecular Biology

Fort Collins, CO 80523-1870

USA

Martijn S. Luijsterburg

Department of Toxicogenetics

Leiden University Medical Center

2300 RC Leiden

The Netherlands

and

Karolinska Institutet

Department of Cell and Molecular Biology

17177

Stockholm

Sweden

John F. Marko

Northwestern University

Department of Molecular Biosciences and

Department of Physics and Astronomy

Evanston, IL 60208

USA

John S. Mattick

Institute for Molecular Bioscience

The University of Queensland

Brisbane QLD 4072

Australia

Karl Nightingale

Institute of Biomedical Research

University of Birmingham Medical School

Birmingham B15 2TT

United Kingdom

Karsten Rippe

Deutsches Krebsforschungszentrum (DKFZ) & BioQuant

Research Group Genome Organization and Function

Im Neuenheimer Feld 280

69120 Heidelberg

Germany

Eric C. Schirmer

University of Edinburgh

The Wellcome Trust Centre for Cell Biology

Edinburgh EH9 3JR

United Kingdom

Ute Schmidt

Institut de Génétique Moléculaire de Montpellier

CNRS UMR 5535

1919, route de Mende

34293 Montpellier Cedex 5

France

Michael Snyder

Stanford University School of Medicine

Department of Genetics

Stanford, CA 94305

USA

Fabio Spada

Center for Integrated Protein Science Ludwig Maximilians University Munich

Department of Biology

82152 Planegg-Martinsried

Germany

Hilmar Strickfaden

Department of Oncology

University of Alberta Cross Cancer Institute

Edmonton

Alberta T6G 1Z2

Canada

Mariliis Tark-Dame

University of Amsterdam

Swammerdam Institute for Life Sciences

1090 GE Amsterdam

The Netherlands

Vladimir B. Teif

Deutsches Krebsforschungszentrum (DKFZ) & BioQuant

Research Group Genome Organization and Function

Im Neuenheimer Feld 280

69120 Heidelberg

Germany

and

Institute of Bioorganic Chemistry

Belarus National Academy of Sciences

Kuprevich 5/2

220141 Minsk

Belarus

Roel van Driel

University of Amsterdam

Swammerdam Institute for Life Sciences

1090 GE Amsterdam

The Netherlands

Silvana van Koningsbruggen

Wellcome Trust Centre for Gene

Regulation and Expression, College of Life Sciences

University of Dundee

Dundee DD1 5EH

United Kingdom

Beth Weiner

Harvard University

Department of Molecular and Cellular Biology

Cambridge, MA 02138

USA

Belinda J. Westman

Wellcome Trust Centre for Gene

Regulation and Expression

College of Life Sciences

University of Dundee

Dundee DD1 5EH

United Kingdom

Liangran Zhang

Harvard University

Department of Molecular and Cellular Biology

Cambridge, MA 02138

USA

Denise Zickler

Université Paris-Sud

Institut de Génétique et Microbiologie, UMR8621

Orsay

France

Nikolaj Zuleger

University of Edinburgh

The Wellcome Trust Centre for Cell Biology

Edinburgh EH9 3JR

United Kingdom

Chapter 1

Deciphering DNA Sequence Information

Mark Kaganovich and Michael Snyder

1.1 Introduction

The revolution in DNA sequencing technologies during the past decade and a half has resulted in an outburst of genome sequence information for more than 800 organisms. Genomes of many humans from different ethnic backgrounds have been sequenced at varying degrees of coverage using multiple technological platforms and strategies and the effort is ongoing; thousands of human genomes will be available in the next few years for researchers to analyze. A major challenge ahead is to determine the functional components of the different genome sequences and how they vary across individuals and species.

Traditionally most efforts have focused on the analysis of protein-coding genes. These are typically annotated as exons separated by introns. Genes are transcribed into messenger RNA (mRNA), the introns are spliced out, and the exons are translated to protein. In addition we now know there is a plethora of information in non-coding DNA sequence as to how to regulate the expression of the gene-coding regions. In this chapter we cover the major categories of genomic sequence and the methods used to investigate them.

1.2 Genes and Transcribed Regions

Genes are transcribed regions of the genome that are made up of exons and introns. Exons are arranged linearly on the transcribed portion of the DNA separated by introns. The entire region is transcribed, the introns are spliced out by the cellular splicing machinery, a poly-A tail is added to the 3′ end of the RNA, and a modified guanine is added to the 5′ end, termed the 5′ cap. The resulting mRNA is exported from the nucleus into the cytoplasm and translated.

1.2.1 Open Reading Frames

It is thought that the human genome is made up of roughly 20 000 distinct protein-coding genes, though this number is greatly increased when considering the many protein-coding combinations that result from alternate splicing of introns (Chapter 11). This means that if exons A, B, and C make up a gene, two isoforms could be the exons A and B spliced together and the exons A and C spliced together. The average human exon length in humans is 140 bp. The median intron length is ∼1000 bp [1]. The average is approximately 3000 bp, due to the long tail of the intron lengths distribution [1]. There are some introns that are greater than 100 000 bp and <10% are longer than 11 000 bp [1, 2]. Recent evidence suggests that >90% of human genes have alternate splicing isoforms that are spliced in a tissue-dependent manner [3, 4]. The exons in a gene that are spliced together into an mRNA and then translated to protein are referred to as an open reading frame (ORF), distinguished by the often species-specific start and stop codons.

Mapping transcribed regions of the genome and the ORFs contained within them is an important challenge in genomics. It is necessary for our fundamental understanding of cellular function; we cannot understand the cell without knowing its protein components that are coded for by genes. Recent work in our laboratory on high-throughput sequencing of the model system yeast Saccharomyces cerevisiae transcriptome has helped reveal the complex nature of ORF organization in eukaryotic cells [4, 5]. Nagalakshmi et al. sequenced and quantified the transcriptome of S. cerevisiae (under rich media conditions) by capturing and reverse-transcribing poly-adenylated mRNA and then fragmenting and sequencing the cDNA (using the Illumina high-throughput sequencing platform). The resulting 35-bp sequencing reads were mapped to the genomic sequence. The mapping is thought to represent much of the transcribed region of the genome, not including non-polyadenylated RNAs such as microRNAs (miRNA) and ribosomal RNA (rRNA). Since polyadenylation is a requirement for mRNA export from the nucleus (with the exception of histone mRNAs), these regions should include all translated ORFs. Some of the RNAs are likely non-coding regulatory RNAs that are also polyadenylated, such as long interfering non-coding RNAs (lincs) [6].

1.2.2 Mapping Transcriptional Start Sites

Sequencing transcribed RNA (RNA-Seq) has helped map the location of transcriptional start sites in the genome, which is integral for our understanding of transcriptional promoter structure and thus gene expression regulation [3, 5]. The yeast genome includes many overlapping transcripts transcribed from opposite strands of the DNA [5]. Because many of these are antisense it is expected that they form double-stranded RNA (dsRNA) species. This phenomenon is likely also present in mammalian genomes, which is surprising given the role of dsRNA in triggering the RNA interference machinery in many eukaryotes that silences gene expression and in potentially triggering viral immune responses [7, 8].