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Epigenetics is a term in biology referring to heritable traits that do not involve changes in the underlying DNA sequence of the organism. Epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance. The "epigenome" is a parallel to the word "genome," and refers to the overall epigenetic state of a cell. Cancer and stem cell research have gradually focused attention on these genome modifications. The molecular basis of epigenetics involves modifications to DNA and the chromatin proteins that associate with it. Methylation, for example, can silence a nearby gene and seems to be involved in some cancers.
Epigenetics is beginning to form and take shape as a new scientific discipline, which will have a major impact on Medicine and essentially all fields of biology. Increasingly, researchers are unearthing links between epigenetics and a number of diseases.
Although in recent years cancer has been the main focus of epigenetics, recent data suggests that epigenetic plays a critical role in psychology and psychopathology. It is being realized that normal behaviors such as maternal care and pathologies such as Schizophrenia and Alzheimer's might have an epigenetic basis. It is also becoming clear that nutrition and life experiences have epigenetic consequences.
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Encyclopedia of Molecular Cell Biology and Molecular Medicine.
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Table of Contents
Related Titles
Title Page
Copyright
Preface and Commentary
List of Contributors
Volume I
Part I: Analytical Methods
1 RNA Methodologies
1 Introduction
2 Subpopulations of RNA
3 Goals in the Purification of RNA
4 Methods of Cellular Disruption and RNA Recovery
5 Inhibition of Ribonuclease Activity
6 Methods for the Analysis of RNA
7 Summary
References
2 AR All Things ChIP
1 Introduction
2 Protein-DNA Binding
3 ChIP Protocol
4 ChIP-PCR, ChIP-Chip, or ChIP-Seq. Which Should be Chosen?
5 Experimental Considerations
6 Calculating IP Enrichment
7 Special Analysis Considerations
8 Conclusions
References
3 Methods for DNA Methylation Analysis
1 Introduction
2 Methods of DNA Methylation Analysis
3 Concluding Remarks
Acknowledgments
References
4 DNA Methylation Analysis by MALDI Mass Spectrometry
1 Introduction to DNA Methylation
2 Epigenetics and Disease
3 DNA Methylation Content Analysis by Mass Spectrometry
4 Specific DNA Methylation Analysis
5 Introduction to MALDI
6 Problems of MALDI Analysis of DNA
7 DNA Sequencing with MALDI Mass Spectrometry Readout
8 Primer Extension for the Interrogation of Specific Positions
9 Quantification
10 Automation of Sample Preparation, Data Accumulation, and Analysis
11 Positioning of MALDI MS for DNA Methylation Analysis
12 Applications of DNA Methylation Analysis by Mass Spectrometry
13 DNA Methylation Analysis for Tumor Classification
14 DNA Methylation Analysis for Prognosis and Response to Treatment
15 Prenatal Diagnosis
16 Conclusions
References
5 Tag Sequencing
1 Library Construction
2 Advanced Sequencing Technologies
3 Data Analysis and Bioinformatics
4 Applications of Tag Sequencing
5 Clinical Applications of Tag Sequencing
6 Future Perspectives
Acknowledgments
References
Part II: Basic Molecular Mechanisms
6 Heterochromatin and Euchromatin—Organization, Boundaries, and Gene Regulation
1 Properties and Functions of Heterochromatin
2 Euchromatin Formation
3 Boundaries between Heterochromatin and Euchromatin
4 Insulating against Active Chromatin
Acknowledgments
References
7 Regulation of Gene Expression
1 Introduction
2 Regulation of Gene Expression in Prokaryotes
3 Regulation of Gene Expression in Eukaryotes
4 RNA Splicing
5 Role of microRNAs (miRNAs) in the Regulation of Gene Expression
6 Chromatin Structure and the Control of Gene Expression
7 Epigenetic Control of Gene Expression
8 Gene Regulation by Hormonal Action
9 Post-Transcriptional Regulation of mRNA
10 Transport of Processed mRNA to the Cytoplasm
11 Regulation of Gene Expression at the Level of Translation
Acknowledgments
References
8 Molecular Genetics of Genomic Imprinting
1 Genomic Imprinting in Mammals
2 Imprinted Genes
3 Molecular Mechanisms
4 Imprinting and Disease
5 Human Reproduction
6 Evolution of Imprinting
References
9 Nuclear Transfer for Cloning Animals
1 Introduction and Brief Historical Overview
2 Key Elements and Critical Aspects of NT Technology
3 Applications of NT in Different Species
4 Future Perspectives of NT
Acknowledgments
References
10 Regulation of Gene Expression at the Beginning of Mammalian Development
1 Preimplantation Development
2 Maternal to Zygotic Gene Transition
3 “Zygotic Clock”: The Time-Dependent Activation of Zygotic Gene Expression
4 Developmental Acquisition of Transcriptional Regulation
5 Transition from Morula to Blastocyst Requires Specification of Two Cell Lineages
6 Conclusions and Perspectives
References
11 RNA Interference in Animals
1 Introduction
2 Small Interfering RNA (siRNA)-Mediated Gene Silencing
3 MicroRNA (miRNA)-Mediated Gene Silencing
4 PIWI-Interacting RNA (piRNA)-Mediated Gene Silencing
5 Conclusions
References
12 AR The Cell Nucleus
1 Introduction
2 Nuclear Function
3 Nuclear Structure
4 Integrating Nuclear Structure and Function
5 Overview
References
13 Chromosome Territory Organization within the Nucleus
1 Origins of Chromosome Research
2 Chromosome Territories: An Early Concept and Its Late Experimental Proof
3 Nonrandom, Higher-Order Chromatin Arrangements in Cultured Cells
4 Chromosome Territory Arrangements Change during Normal Development and Cell Differentiation
5 Chromatin Fibers, Loops, and Domains: What Hierarchies, Structures, and Sizes?
6 Capturing Genome-Wide DNA–DNA and DNA–Protein Interactions
7 Functional Nuclear Organization Studied by Electron Microscopy
8 Functional Nuclear Organization Studied by Light Optical Nanoscopy
9 Where We Stand: Current Models of the Functional Nuclear Organization
10 A Glance at the Future: Nuclear Cartography with Nanometer Resolution
References
14 Epigenetic Reprogramming in Mammalian Development
1 Introduction
2 Epigenetic Reprogramming in Preimplantation Embryos
3 Epigenetic Reprogramming in PGCs
4 Mechanistic Aspects of DNA Methylation Reprogramming
5 Conclusions
References
15 Histone Acetylation and Deacetylation
1 Introduction
2 Histone Acetyltransferases (HATs): “Writers”
3 Histone Deacetylases (HDACs): “Erasers”
4 Epigenetic Therapies: Histone Acetylation–Deacetylation and Disease
5 Summary
References
16 Epigenetic Regulation in Pluripotent Stem Cells
1 Introduction
2 DNA Methylation
3 Histone Modifications and Histone Variants
4 Higher-Order Structure of Chromatin
5 X-Chromosome Inactivation
6 Regulation of ESC Pluripotency and Differentiation by miRNAs
7 Telomere Function and Genomic Stability in ESCs
8 Imprinting and ESC Stability
9 Epigenetic Interconversion among Mouse ESCs, EpiSCs, and Human ESCs
10 Summary
References
17 Imprinting and the Epigenetic Asymmetry between Parental Genomes
1 Introduction
2 Evolution of Genomic Imprinting in Mammals
3 Asynchronous Replication of Imprinted Chromosome Domains
4 DNA Methylation and Chromatin Structure
5 Imprinting Mechanisms and Their Disturbances
6 The Imprinting Cycle
7 Reprogramming Errors and Epigenetic Variation
References
18 Chromatin Dynamics and Higher-Order Chromatin Organization
1 Introduction
2 Structural Levels of Chromatin Organization
3 Chromatin Dynamics
4 Conclusions
Acknowledgments
References
19 Histone Modifications
1 Introduction
2 Histone Acetylation
3 Histone Methylation
4 Histone Phosphorylation
5 Other Histone Modifications
6 Histone Modifications in DNA Processes
7 Histone Modifications and Disease
8 Perspective
References
20 Monozygotic Twins and Epigenetics
1 Introduction
2 Twin Formation
3 The Epigenome
4 The Impact of Environment on the Epigenome
5 Monozygotic Twins and Epigenetic Inheritance
6 Monozygotic Twins and Aging
7 Monozygotic Twins in Research Studies
8 Monozygotic Twins and Complex Diseases
9 Future Directions
References
21 Prions as Epigenetic Regulators of Phenotype in Fungi
1 Prions: An Introduction
2 Prions Regulate a Variety of Biological Processes in Fungi
3 Distinguishing Features of Prion Proteins
4 Molecular Mechanisms of Prion Inheritance
5 Prions: Beyond Fungi
Acknowledgments
References
Volume 2
Part III: The Epigenome
22 Computational Epigenetics
1 Introduction
2 Data Sources
3 Computational Tools
4 Computational Analysis of DNA Methylation
5 Computational Analysis of Histone Modifications
6 Computational Analysis of Cancer Epigenetics
7 Computational Analysis of Stem Cell Epigenetics
8 Conclusion
References
23 The Human Epigenome
1 Introduction
2 DNA Methylation
3 DNA Methylation in Normal Development
4 Nutrition and DNA Methylation
5 Epigenetic Crosstalk: DNA Methylation and Histone Modifications
6 Genome-Wide DNA Methylation Analyses
7 Computational Analysis of the Methylome
8 DNA Methylation in Cancer
9 DNA Methylation as a Biomarker
10 Epigenetic Response to Cancer Therapy
11 Concluding Remarks
References
24 Methylomes
1 An Introduction to Methylomes
2 Technology
3 Applications
4 Future Directions
References
Part IV: Medical Applications
25 Emerging Clinical Applications and Pharmacology of RNA
1 Clinically Relevant Features of RNA
2 Emerging Clinical Applications of RNA
3 The Design, Synthesis, Delivery, and Pharmacokinetics of RNA
4 An RNA Drug for Every Disease?
Acknowledgments
References
26 Epigenetics of the Immune System
1 The Immune System: An Introduction
2 Epigenetic Markings
3 HSCs: Epigenetic Basis for Stem Cell Characteristics
4 B Cells
5 T Cells
6 Conclusions
References
27 Epigenetic Medicine
1 Introduction to the Epigenome
2 The Epigenome: A Biomarker for Exposure
3 Targeting the Epigenome in Complex Disease
4 Cancer as an Epigenetic Disease
5 Summary
References
28 Chromatin Remodeling in Carcinoma Cells
1 Introduction
2 Chromatin
3 Chromatin Remodeling
4 Remodeling the Hallmarks of Cancer
5 Conclusion
References
29 Pharmaco-Epigenomics to Improve Cancer Therapies
1 Introduction
2 The Epigenetic Origin of Cancer
3 Pharmaco-Epigenomics: Translating Epigenetics into Clinical Practice
4 Epigenetic Therapies for Cancer
5 Epigenetic Biomarkers for Cancer Therapy
6 Epigenetic Therapy beyond Cancer Cells
7 Future Perspectives
References
Part V: Model Organisms
30 Parental Genomic Imprinting in Flowering Plants
1 General Context of Parental Genomic Imprinting in Plants
2 Imprinted Genes and Their Function
3 Molecular Mechanisms Controlling Imprinting
4 Biological Significance and the Evolution of Imprinting
Acknowledgments
References
31 Epigenetics of Filamentous Fungi
1 Genome Defense in Filamentous Fungi
2 Epigenetic Phenomena in Filamentous Fungi
3 Parts of the Machinery: Proteins Involved in Silencing
4 Propagation of Epigenetic Marks in Filamentous Fungi
5 RNA-Dependent Silencing Phenomena
6 Transcriptional Silencing or Activation by Changes in Chromatin Structure
7 Concluding Remarks
Acknowledgments
References
Epigenetic Gene Regulation in Bacteria
1 Epigenetic Variation and Lineage Formation in Bacteria
2 DNA Methylation in Bacteria
3 Bacterial Lineage Formation by Hereditary Transmission of Feedback Loops
4 Phenotypic Heterogeneity of Bacteria in Natural Environments
5 Perspectives
References
33 Epigenetics of Ciliates
1 Ciliate Biology
2 Epigenetic Phenomena in Ciliates
3 RNA-Mediated Epigenetic Mechanisms
4 Small RNA-Mediated DNA Rearrangements
5 Chromosome Fragmentation and Elimination of DNA during Conjugation in Oxytricha
6 Perspective
References
Index
Related Titles
Meyers, R.A. (ed.)
Encyclopedia of Molecular Cell Biology
and Molecular Medicine
Online version: www.meyers-emcbmm.com
Sippl, W., Jung, M. (eds.)
Epigenetic Targets in Drug Discovery
ISBN: 978-3-527-32355-5
Kahl, G.
The Dictionary of Genomics, Transcriptomics and Proteomics
ISBN: 978-3-527-32073-8
Giordano, A., Macaluso (eds.)
Cancer Epigenetics
Biomolecular Therapeutics in Human Cancer
ISBN: 978-0-471-71096-7
Niculescu, M.D., Haggarty, P. (eds.)
Nutrition in Epigenetics
ISBN: 978-0-8138-1605-0
The Editor
Dr. Robert A. Meyers
Editor in Chief
RAMTECH Limited
122, Escalle Lane
Larkspur, CA 94939
USA
Cover
Simplified model of the interplay between histone modifications and small RNAs in the maintenance of pericentric heterochromatin in fission yeast (for more information see Chapter 19 “Histone Modifications”, Figure 8)”. Designed and drawn by Andrew Bannister and Blerta Xhemalce, The Gurdon Institute, University of Cambridge, CB2 1QN, UK.
Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty can be created or extended by sales representatives or written sales materials. The Advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
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All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form — by photoprinting, microfilm, or any other means — nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.
Print ISBN: 978-3-527-32682-2
Preface and Commentary
Epigenetics is the term given to heritable traits that occur over rounds of cell division and sometimes transgenerationally, in which the mechanisms are reversible, but do not involve changes to the underlying DNA sequence. This involves regulatory systems such as DNA methylation, histone modification, nucleosome location, and noncoding RNA. The epigenome, meanwhile, is a parallel to the word genome, refers to the overall epigenetic state of a cell and can be considered essentially a network of chemical switches within our cells.
Our compendium is written for university undergraduates, graduate students, faculty and investigators at research institutes. There are 33 articles with a combined length of over 1100 pages and as such is the largest in depth, up to date treatment of epigenetics presently available.
Epigenetics Regulation and Epigenomics differs in content and quality from all others available in five ways 1) the overall coverage was approved by our Board, which includes 11 Nobel Prize winners; 2) the selection of each article and author was validated by several reviewers from major university research centers; 3) each article was then reviewed by peers from other universities; 4) a glossary of terms with definitions is provided at the beginning of each article and 5) the articles average 35 print pages — which provides several times the depth of other such compendia.
The content is divided into five sections of articles covering key epigenetics areas. These sections are Analytical Methods, Basic Molecular Mechanisms, The Epigenome, Medical Applications and Model Organisms.
Analytical Methods articles range from chromatin immunoprecipitation (ChIP), to tag sequencing (impacting epigenomics), DNA methylation analysis, high throughput epigenotyping by mass spectrometry and includes RNA methodologies which provide an understanding of aspects of gene regulation. The Basic Mechanisms section covers the cell nucleus and chromatin organization and dynamics; epigenetics of stem cells; imprinting and histone modifications and methylation; as well as epigenetic aspects of prions, twins, cloning and RNA interference and all types of regulation of gene expression. The Epigenome coverage includes computational epigenetics and the human epigenome. Medical Applications include a comprehensive article on epigenetic medicine and additional detail in several articles on the of epigenetics of cancer, the immune system and aging as well as pharmaco-epigenomics to improve cancer therapies. In fact, drugs that inhibit the DNA methyltransferases, which place methyl groups on the DNA, are now approved for clinical use in the United States for the treatment of certain cancers. This may be the beginning of a new era of cancer treatment involving epigenetic therapy. Pharmacology and emerging clinical application of RNA is also presented in this section. Model Organisms range from bacteria to protozoans as well as fungi and plants.
Our team of authors and peer reviewers are located at top rated epigenetics departments at institutions including the University of Cambridge, the University of Southern California, the University of California at Los Angeles, Washington University, St. Louis, and the National Institutes of Health. The team is truly global with authors or coauthors from the U.S., Sweden, Belgium, Germany, France, the UK, Austria, Spain, Hungary, Japan, India, China, Singapore, Canada and Israel.
Our team hopes that you, the reader, will benefit from our hard work — finding the content useful in your research as well as educational. We wish to thank our Managing Editor, Sarah Mellor, as well as our Executive Editor, Gregor Cicchetti for both their advice and hard work in the course of this project.
Larkspur, California, March 2012
Robert A. Meyers
RAMTECH Limited
List of Contributors
Volume 1
Part I
Analytical Methods
1
RNA Methodologies
Robert E. Farrell, Jr.
Penn State University, Department of Biology, 1031, Edgecomb Avenue, NY, PA 17403, USA
1 Introduction
2 Subpopulations of RNA
2.1 Messenger RNA (mRNA)
2.2 Transfer RNA (tRNA)
2.3 Ribosomal RNA (rRNA)
2.4 Nuclear RNA
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