EpigenomicsFrom Chromatin Biology to Therapeutics
Understanding mechanisms of gene regulation that are independent of the DNA
sequence itself – epigenetics – has the potential to overthrow long-held views on
central topics in biology, such as the biology of disease or the evolution of species.
High-throughput technologies reveal epigenetic mechanisms at a genome-wide level,
giving rise to epigenomics as a new discipline with a distinct set of research questions
and methods. Leading experts from academia and from the biotechnology and phar-
maceutical industries explain the role of epigenomics in a wide range of contexts,
covering basic chromatin biology, imprinting at a genome-wide level, and epigenom-
ics in disease biology and epidemiology. Details on assays and sequencing technology
serve as an up-to-date overview of the available technological tool kit. A reliable guide
for newcomers to the field as well as experienced scientists, this is a unique resource for
anyone interested in applying the power of twenty-first-century genomics to epi-
genetic studies.
KR I SHNARAO APPASAN I is the Founder and Chief Executive Officer of GeneExpression
Systems, a conference-producing organization focusing on biomedical and physical
sciences. He is editor of MicroRNAs: From Basic Science to Disease Biology (2007) and
RNA Interference: From Basic Science to Drug Development (2005), also published by
Cambridge University Press.
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Epigenomics
FROM CHROMATIN BIOLOGY TO THERAPEUTICS
Edited by
Krishnarao AppasaniGeneExpression Systems, Inc.
Foreword by
Azim SuraniUniversity of Cambridge
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Cambridge University Press978-1-107-00382-8 - Epigenomics: From Chromatin Biology to TherapeuticsEdited by Krishnarao AppasaniFrontmatterMore information
CAMBR IDGE UN IV E R S I T Y P R E S S
Cambridge, New York, Melbourne, Madrid, Cape Town,
Singapore, São Paulo, Delhi, Mexico City
Cambridge University Press
The Edinburgh Building, Cambridge CB2 8RU, UK
Published in the United States of America by Cambridge University Press, New York
www.cambridge.org
Information on this title: www.cambridge.org/9781107003828
© Cambridge University Press 2012
This publication is in copyright. Subject to statutory exception
and to the provisions of relevant collective licensing agreements,
no reproduction of any part may take place without the written
permission of Cambridge University Press.
First published 2012
Printed in the United Kingdom at the University Press, Cambridge
A catalogue record for this publication is available from the British Library
Library of Congress Cataloguing in Publication data
Epigenomics, from chromatin biology to therapeutics / edited by Krishnarao
Appasani.
p. cm.
Includes bibliographical references and index.
ISBN 978-1-107-00382-8 (alk. paper)
1. Epigenetics. 2. Gene expression. I. Appasani, Krishnarao, 1959–
QH450.E66 2012
572.8065–dc232012013324
ISBN 978-1-107-00382-8 Hardback
Cambridge University Press has no responsibility for the persistence or
accuracy of URLs for external or third-party internet websites referred to
in this publication, and does not guarantee that any content on such
websites is, or will remain, accurate or appropriate.
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In memory of:
My mentor, Late Har Gobind KhoranaMassachusetts Institute of Technology, USAWinner of the Nobel Prize in Physiology or Medicine, 1968
and
My friend, Late Marshall NirenbergNational Institutes of Health, USAWinner of the Nobel Prize in Physiology or Medicine, 1968
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Contents
List of contributors page x
Foreword by Azim Surani xxv
Preface xxvii
I Basics of chromatin biology and biochemistry 1
1 Introduction to epigenomics
Krishnarao Appasani and Raghu K. Appasani 3
2 Epigenetics and its historical perspectives
Robin Holliday 19
3 Functional networks of human epigenetic factors
Andrey Poleshko, Natalia Shalginskikh, and Richard A. Katz 30
4 Nucleosome positioning in promoters: significance and open questions
Jun S. Song and David E. Fisher 47
5 Chemical reporters of protein methylation and acetylation
Markus Grammel, Yu-Ying Yang, and Howard C. Hang 60
6 Long non-coding RNA in epigenetic gene silencing
Takashi Nagano 73
II Epigenomic imprinting and stem cells 89
7 Active DNA demethylation: the enigma starts in the zygote
Julia Arand, Konstantin Lepikhov, Mark Wossidlo, and Jörn Walter 91
8 Histone modifications of lineage-specific genes in human embryonic
stem cells during in vitro differentiation
Hyemin Kim, Hogyu Seo, Daeyoup Lee, and Yong-Mahn Han 104
9 Epigenetic stability of human pluripotent stem cells
Céline Vallot and Claire Rougeulle 118
10 Impact of CpG methylation in addressing adipose-derived stem cell
differentiation towards the cardiac phenotype
Alice Pasini, Francesca Bonafè, Emanuela Fiumana, Carlo Guarnieri, Paolo
G. Morselli, Carlo M. Oranges, Claudio M. Caldarera, Claudio Muscari, and
Emanuele Giordano 134
vii
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11 Regulation of the stem cell epigenome by REST
Angela Bithell and Noel J. Buckley 146
12 MicroRNAs in embryonic stem cells
Shari Orlanski and Yehudit Bergman 163
13 Regulation of timing of replication
Rituparna Mukhopadhyay and Eric E. Bouhassira 179
III Epigenomic assays and sequencing technology 195
14 Detection of CpG methylation patterns by affinity capture methods
Luis G. Acevedo, Ana Sanz, Dylan Maixner, Kornel Schuebel, Mary
A. Jelinek, David Goldman, and Joseph M. Fernandez 197
15 Genome-wide ChIP-DSL profiling of promoter methylation patterns
associated with cancer and stem cell differentiation
Jeffrey D. Falk 210
16 Quantitative, high-resolution CpG methylation assays on the
pyrosequencing platform
Dirk Löffert, Ralf Peist, Thea Rütjes, Norbert Hochstein, Dorothee Honsel,
Frank Narz, Ioanna Andreou, Richard Kroon, Andreas Missel, Andrea
Linnemann-Florl, Lennart Suckau, and Gerald Schock 223
17 DNA methylation profiling using Illumina BeadArray platform
Marina Bibikova, Jian-Bing Fan, and Kevin L. Gunderson 235
18 Advances in capillary electrophoresis-based methods for DNA
methylation analysis
Benjamin G. Schroeder, Victoria L. Boyd, and Gerald Zon 249
19 Genome-wide methylome analysis based on new high-throughput
sequencing technology
Mingzhi Ye, Fei Gao, Xu Han, Guanyu Ji, Zhixiang Yan, and Honglong Wu 260
20 Three-dimensional quantitative DNA methylation imaging for
chromatin texture analysis in pharmacoepigenomics and
toxicoepigenomics
Jian Tajbakhsh and Arkadiusz Gertych 273
IV Epigenomics in disease biology 291
21 Cancer classification by genome-wide and quantitative DNA
methylation analyses
Atsushi Kaneda 293
22 Promoter CpG island methylation in colorectal cancer: biology and
clinical applications
Sarah Derks and Manon van Engeland 306
23 The epigenetic profile of bladder cancer
Ewa Dudziec and James W. F. Catto 323
24 Genome-scale DNA methylation analyses of cancer in children
Nicholas C. Wong and David M. Ashley 338
25 The epigenetics of facioscapulohumeral muscular dystrophy
Weihua Zeng, Alexander R. Ball, Jr., and Kyoko Yokomori 347
26 Modulating histone acetylation with inhibitors and activators
B. Ruthrotha Selvi, D. V. Mohankrishna, and Tapas K. Kundu 362
viii Contents
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V Epigenomics in neurodegenerative diseases 389
27 Study design considerations in epigenetic studies of neuropsychiatric
disease
Fatemeh Haghighi, Sephorah Zaman, and Yurong Xin 391
28 Epigenetic regulation in human neurodevelopmental disorders
including autism, Rett syndrome, and epilepsy
Laura B. K. Herzing 404
29 The neurobiology of chromatin-associated mechanisms in the context
of psychosis and mood spectrum disorders
Schahram Akbarian 420
30 Genome-wide DNA methylation analysis in patients with familial
ATR-X mental retardation syndrome
Gemma Carvill and Andrew Sharp 434
31 Kinases and phosphatases in the epigenetic regulation of cognitive
functions
Tamara B. Franklin and Isabelle M. Mansuy 447
VI Epigenetic variation, polymorphism, and epidemiological perspectives 459
32 Epigenetic effects of childhood abuse on the human brain
Benoit Labonté and Gustavo Turecki 461
33 X-linked expressed single nucleotide polymorphisms and dosage
compensation
Lygia V. Pereira and Joana C. Moreira de Mello 483
34 Epigenomic diversity of colorectal cancer
Aditi Hazra and Shuji Ogino 491
35 Epigenetic epidemiology: transgenerational responses to the
environment
Lars Olov Bygren 505
Index 514
The colour plates are to be found between pages 162 and 163
Contents ix
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Contributors
Luis G. Acevedo
Active Motif, Inc.
1914 Palomar Oaks Way, Suite 150
Carlsbad, CA 92008, USA
Schahram Akbarian
Brudnick Neuropsychiatric Research Institute
Department of Psychiatry
University of Massachusetts Medical School
Worcester, MA 01604, USA
Ioanna Andreou
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
Krishnarao Appasani
GeneExpression Systems, Inc.
PO Box 540170
Waltham, MA 02454, USA
Raghu K. Appasani
GeneExpression Systems, Inc.
PO Box 540170
Waltham, MA 02454, USA
Julia Arand
Saarland University
FR 8.3 Biosciences
Laboratory of EpiGenetics
x
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Campus Building A2.4
Postbox 151150
Saarbrücken, D-66041, Germany
David M. Ashley
Andrew Love Cancer Centre
Deakin University
Geelong, Victoria 3220, Australia
Alexander R. Ball, Jr.
Department of Biological Chemistry
School of Medicine
University of California
Irvine, CA 92697, USA
Yehudit Bergman
Department of Developmental Biology and Cancer Research
Institute for Medical Research Israel-Canada
The Hebrew University Medical School
Jerusalem 91120, Israel
Marina Bibikova
Illumina, Inc.
9885 Towne Centre Drive
San Diego, CA 92121, USA
Angela Bithell
Department of Molecular and Cellular Neurobiology
King’s College London
Institute of Psychiatry
125 Coldharbour Lane
London, SE5 9NU, UK
Francesca BonafèDepartment of Biochemistry “G. Moruzzi”
University of Bologna
via Irnerio, 48
Bologna, I-40126, Italy
Eric E. Bouhassira
Department of Cell Biology
Albert Einstein College of Medicine
1300 Morris Park Ave–Ullmann 903
Bronx, NY 10461, USA
List of contributors xi
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Victoria L. Boyd
Applied Biosystems
850 Lincoln Centre Drive
Foster City, CA 94404, USA
Noel J. Buckley
King’s College London
Institute of Psychiatry
125 Coldharbour Lane
London, SE5 9NU, UK
Lars Olov Bygren
Novum Karolinska Institutet
Unit of Preventive Nutrition
Department of Biosciences and Nutrition
Hälsovägen 7
Huddinge, SE-141 57, Sweden
Claudio M. Caldarera
National Institute for Cardiovascular Research
Bologna, I-40126, Italy
Gemma Carvill
Division of Genetic Medicine
University of Washington
Seattle, WA 98195, USA
James W.F. Catto
Academic Urology Unit
Institute for Cancer Studies
The Medical School
University of Sheffield
Beech Hill Road,
Sheffield, S10 2RX, UK
Sarah Derks
Department of Internal Medicine
VU University Medical Center
1007 MB, Amsterdam, The Netherlands
Ewa Dudziec
Academic Urology Unit
Institute for Cancer Studies
The Medical School
University of Sheffield
xii List of contributors
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Beech Hill Road,
Sheffield, S10 2RX, UK
Jeffrey D. Falk
Aviva Systems Biology
5754 Pacific Center Blvd., Suite 201
San Diego, CA 92121, USA
Presently at: RiboMed Biotechnologies, Inc.
2736 Loker Avenue West, Suite C
Carlsbad, CA 92010, USA
Jian-Bing Fan
Illumina, Inc.
9885 Towne Centre Drive
San Diego, CA 92121, USA
Joseph M. Fernandez
Active Motif, Inc.
1914 Palomar Oaks Way, Suite 150
Carlsbad, CA 92008, USA
David E. Fisher
Massachusetts General Hospital
Harvard Medical School
55 Fruit Street, Bartlett Hall 622
Boston, MA 02114, USA
Emanuela Fiumana
Department of Biochemistry “G. Moruzzi”
University of Bologna
via Irnerio, 48
Bologna, I-40126, Italy
Tamara B. Franklin
Brain Research Institute
University of Zurich/ETH Zurich
Winterthurerstrasse 190
Zürich, CH-8057, Switzerland
Presently at: EMBL Monterotondo
Adriano Buzzati-Traverso Campus
Via Ramarini 32
00015 Monterotondo, Italy
List of contributors xiii
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Fei Gao
Beijing Genomics Institute
Main Building, Beishan Industrial Zone
Yantian District
Shenzhen 518083, P. R. China
Arkadiusz Gertych
Translational Cytomics Group
Department of Surgery
Cedars-Sinai Medical Center
Los Angeles, CA 90048, USA
Emanuele Giordano
University of Bologna
Laboratory of Cellular and Molecular Engineering
via Venezia, 52
Cesena, I-43027, Italy
and
Dipartimento di Biochimica “G. Moruzzi”
via Irnerio, 48
Bologna, I-40126, Italy
David Goldman
Laboratory of Neurogenetics
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
5625 Fisher’s Lane
Rockville, MD 20852, USA
Markus Grammel
Laboratory of Chemical Biology
1230 York Avenue, Box 250
The Rockefeller University
New York, NY 10065, USA
Carlo Guarnieri
Department of Biochemistry “G. Moruzzi”
University of Bologna
via Irnerio, 48
Bologna, I-40126, Italy
Kevin L. Gunderson
Illumina, Inc.
9885 Towne Centre Drive
San Diego, CA 92121, USA
xiv List of contributors
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Victoria (Fatemeh) G. Haghighi
Columbia University Department of Psychiatry
New York State Psychiatric Institute
1051 Riverside Drive, Box 42
New York, NY 10032, USA
Xu Han
Beijing Genomics Institute
Main Building, Beishan Industrial Zone
Yantian District
Shenzhen 518083, P. R. China
Yong-Mahn Han
Department of Biological Sciences
KAIST
335 Gwahangno, Yuseong
Daejeon 305-701, Korea
Howard C. Hang
Laboratory of Chemical Biology
1230 York Avenue, Box 250
The Rockefeller University
New York, NY 10065, USA
Aditi Hazra
Harvard School of Public Health
Channing Laboratory
181 Longwood Avenue, Room 355
Boston, MA 02115, USA
Laura B. K. Herzing
Northwestern University Feinberg School of Medicine
Children’s Memorial Research Center
2300 Children’s Plaza Box 211
Chicago, IL 60614, USA
Norbert Hochstein
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
Robin Holliday
Australian Academy of Sciences
12 Roma Court
West Pennant Hills, NSW 2125, Australia
List of contributors xv
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Dorothee Honsel
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
Mary A. Jelinek
Active Motif, Inc.
1914 Palomar Oaks Way, Suite 150
Carlsbad, CA 92008, USA
Guanyu Ji
Beijing Genomics Institute
Main Building, Beishan Industrial Zone
Yantian District
Shenzhen 518083, P. R. China
Yan Jiang
Brudnick Neuropsychiatric Research Institute
Department of Psychiatry
University of Massachusetts Medical School
Worcester, MA 01604, USA
Atsushi Kaneda
Genome Science Division, RCAST
The University of Tokyo
4-6-1 Komaba, Meguro-ku
Tokyo 153-8904, Japan
Richard A. Katz
Epigenetics and Progenitor Cells Program
Fox Chase Cancer Center, Room R422
333 Cottman Avenue
Philadelphia, PA 19111, USA
Hyemin Kim
Department of Biological Sciences and Center for Stem Cell Differentiation
KAIST
335 Gwahangno, Yuseong
Daejeon 305-701, Korea
Richard Kroon
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
xvi List of contributors
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Tapas K. Kundu
Molecular Biology and Genetics Unit
Jawaharlal Nehru Centre for Advanced Scientific Research
Jakkur, P.O. Bangalore-560 064
Karnataka, India
Benoit LabontéDepartment of Psychiatry
McGill University
Douglas Mental Health Institute
6875 LaSalle Boulevard
Montreal, QC H4H 1R3, Canada
Daeyoup Lee
Department of Biological Sciences
KAIST
335 Gwahangno, Yuseong
Daejeon 305-701, Korea
Konstantin Lepikhov
Saarland University
FR 8.3 Biosciences
Laboratory of EpiGenetics
Campus Building A2.4
Postbox 151150
Saarbrücken, D-66041, Germany
Andrea Linnemann-Florl
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
Dirk Loeffert
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
Dylan Maixner
Laboratory of Neurogenetics
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
5625 Fisher’s Lane
Rockville, MD 20852, USA
List of contributors xvii
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Isabelle M. Mansuy
Brain Research Institute
University of Zürich/Swiss Federal Institute of Technology Zürich
Winterthurerstrasse 190
Zürich, CH-8057, Switzerland
Andreas Missel
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
D.V. Mohankrishna
Molecular Biology and Genetics Unit
Jawaharlal Nehru Centre for Advanced Scientific Research
Jakkur, P.O. Bangalore-560 064
Karnataka, India
Joana Carvalho Moreira de Mello
Department of Genetics and Evolutionary Biology
Institute of Bioscience
University of São Paulo
Rua do Matão, 277 sala 350
São Paulo, SP 05508-900, Brazil
Paolo G. Morselli
School of Plastic Surgery
University of Bologna
Bologna, I-40126, Italy
Rituparna Mukhopadhyay
Department of Cell Biology
Albert Einstein College of Medicine
1300 Morris Park Avenue, Ullmann 903
Bronx, NY 10461, USA
Claudio Muscari
Department of Biochemistry “G. Moruzzi”
University of Bologna
via Irnerio, 48
Bologna, I-40126, Italy
Takashi Nagano
Nuclear Dynamics Programme
The Babraham Institute
Babraham Research Campus
Cambridge, CB22 3AT, UK
xviii List of contributors
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Frank Narz
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
Shuji Ogino
Department of Pathology
Brigham and Women’s Hospital, Harvard Medical School
75 Francis Street
Boston, MA 02115, USA
Carlo M. Oranges
School of Plastic Surgery
University of Bologna
Bologna, I-40126, Italy
Shari Orlanski
Developmental Biology and Cancer Research
Medical School
Hebrew University of Jerusalem
Jerusalem, Israel
Alice Pasini
Laboratory of Cellular and Molecular Engineering
University of Bologna, Campus of Cesena
via Venezia, 52
Cesena, I-43027, Italy
and
Department of Biochemistry “G. Moruzzi”
University of Bologna
via Irnerio, 48
Bologna , I-40126, Italy
Ralf Peist
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
Lygia V. Pereira
Departimento di Genética e Biologia Evolutiva
Instituto de Biociências, USP
Rua do Matão, 277 sala 350
São Paulo, SP 05508-900, Brazil
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Andrey Poleshko
Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia, PA 19111, USA
Claire Rougeulle
UMR 7216 Epigenetics and Cell Fate
CNRS/Université Paris Diderot
Bâtiment Lamarck, Case 7042
35 rue Hélène Brion
75013 Paris Cedex 13, France
Thea RütjesQIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
Ana Sanz
Active Motif, Inc.
1914 Palomar Oaks Way, Suite 150
Carlsbad, CA 92008, USA
Benjamin G. Schroeder
NUGEN Technologies Inc.
201 Industrial Road, Suite 310
San Carlos, CA 94070, USA
Gerald Schock
Epigenetics and Whole Genome Amplification
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
Kornel Schuebel
Laboratory of Neurogenetics
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
5625 Fisher’s Lane
Rockville, MD 20852, USA
B.Ruthrotha Selvi
Molecular Biology and Genetics Unit
Jawaharlal Nehru Centre for Advanced Scientific Research
Jakkur, P.O. Bangalore-560 064
Karnataka, India
xx List of contributors
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Hogyu Seo
Department of Biological Sciences
KAIST
335 Gwahangno, Yuseong
Daejeon 305-701, Korea
Natalia Shalginskikh
Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia, PA 19111, USA
Andrew Sharp
Division of Human Genetics
Department of Clinical Laboratory Sciences
University of Cape Town Medical School
Cape Town, South Africa
Presently at: Department of Genetics and Genomic Sciences
Mount Sinai School of Medicine
New York, NY 10002, USA
Jun S. Song
Institute for Human Genetics
Department of Epidemiology and Biostatistics
University of California–San Francisco
San Francisco, CA 94107, USA
Lennart Suckau
QIAGEN GmbH
QIAGEN Strasse 1
Hilden, D-40724, Germany
Azim Surani
The Gurdon Institute
University of Cambridge
Tennis Court Road
Cambridge, CB2 1QN, UK
Jian Tajbakhsh
Group Translational Cytomics
Department of Surgery
Cedars-Sinai Medical Center
Los Angeles, CA 90048, USA
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Gustavo Turecki
McGill Group for Suicide Studies
Department of Psychiatry
McGill University
Douglas Mental Health Institute
6875 LaSalle Boulevard
Montreal, QC H4H 1R3, Canada
Céline Vallot
UMR 7216 Epigenetics and Cell Fate
CNRS/Université Paris Diderot
Bâtiment Lamarck, Case 7042
35 rue Hélène Brion
75013 Paris Cedex 13, France
Manon van Engeland
GROW-School for Oncology and Developmental Biology
Maastricht University Medical Center
6221 LK, Maastricht, The Netherlands
Jörn Walter
Saarland University
Laboratory of Epigenetics
Campus Building A2.4
Postbox 151150
Saarbrücken, D-66041, Germany
Nicholas C. Wong
Postdoctoral Fellow
Developmental Epigenetics, Early Development and Disease
Murdoch Childrens Research Institute
The Royal Children’s Hospital
Flemington Road
Parkville, Victoria 3052, Australia
Mark Wossidlo
Saarland University
FR 8.3 Biosciences
Laboratory of Epigenetics
Campus Building A2.4
Postbox 151150
Saarbrücken, D-66041, Germany
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Honglong Wu
Beijing Genomics Institute
Main Building, Beishan Industrial Zone
Yantian District
Shenzhen 518083, P. R. China
Yurong Xin
Columbia University Department of Psychiatry
New York State Psychiatric Institute
1051 Riverside Drive, Box 42
New York, NY 10032, USA
Zhixiang Yan
Beijing Genomics Institute
Main Building, Beishan Industrial Zone
Yantian District
Shenzhen 518083, P. R. China
Yu-Ying Yang
Laboratory of Chemical Biology
1230 York Avenue, Box 250
The Rockefeller University
New York, NY 10065, USA
Mingzhi Ye
Beijing Genomics Institute
Main Building, Beishan Industrial Zone
Yantian District
Shenzhen 518083, P. R. China
Kyoko Yokomori
Department of Biological Chemistry
School of Medicine
University of California–Irvine
Irvine, CA 92697, USA
Sephorah Zaman
Columbia University Department of Psychiatry
New York State Psychiatric Institute
1051 Riverside Drive, Box 42
New York, NY 10032, USA
Weihua Zeng
Department of Biological Chemistry
School of Medicine
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University of California–Irvine
Irvine, CA 92697, USA
Gerald Zon
Formerly at: Life Technologies
850 Lincoln Center Drive
Foster City, CA 94404, USA
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Foreword
Each cell type in an individual organism has a unique epigenome, although they
share identical genetic information. Epigenomes are established by heritable but
reversible modifications of DNA and histones that affect gene expression without
altering the DNA sequence. Epigenetics is currently one of themost exciting areas
of biological research. These advances in research teach us how the genetic
information or the code is interpreted to generate diversity of cells and tissues.
Epigenomes can change in response to environmental factors such as signaling
molecules to elicit an appropriate response during development and specification
of cell fates. Unlike genetic mutations, epimutations are reversible, which indi-
cates that epigenetic regulation of gene expression can be manipulated. This
provides one of the reasons why advances in basic mechanisms will lead to
advances in biomedicine, through discovery of agents that can affect and alter
the epigenome and gene transcription in diseased tissues, including those aber-
rant modifications that accumulate in the course of aging.
In this book, KrishnaraoAppasani has assembled a stellar group of researchers to
provide their expert views on the current status of the field and on some of the
likely advances in the future. Among the contributors to the book is Robin
Holliday, a pioneer in the field of epigenetics through his work on DNA methyl-
ation, a heritable but reversible DNAmodification of great importance in develop-
ment and disease. Hewrites about epigenetics from a historical perspective. At the
same time, Jörn Walter and colleagues present aspects on how DNA methylation
can be erased. This is currently a major area of research, especially in the context
of enzymes that convert 5-methylcytosine to 5-hydroxymethylcytosine. There is
also a discussion on the emerging field of long non-coding RNAs that are likely to
play a significant role in inducing epigenetic changes.
Epigenomics: From Chromatin Biology to Therapeutics provides expert reviews on
many other diverse areas, whichwill serve as a valuable compendium. This book is
very timely, as it captures some of the spectacular advances in epigenetics, which
have led to unraveling the mechanistic basis for some of the phenomena such
as genomic imprinting. The book also covers advances in chromatin biology,
new techniques andmethods that can be used to carry out genome scale analysis.
These advances are relevant tomany areas of developmental biology, regenerative
medicine, and stem cell research. What are the mechanisms that ensure
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self-renewal of stem cells, and how do epigenetic mechanisms contribute to the
differentiation of diverse cell types from undifferentiated cells? Conversely, what
is the role of epigenetic mechanisms in the reprogramming of somatic cells to
pluripotent stem cells, which is an area of great potential for progress in regener-
ative medicine? This is also critical for understanding the basis of some of human
diseases, including cancers and neurodegenerative disorders.
These advances will also ultimately lead to a better understanding of epigenetic
modifications induced by environmental factors, and their apparent subsequent
inheritance through the germline to affect subsequent generations. Such trans-
generational epigenetic inheritance phenomena, which could be of great impor-
tance for human diseases, are currently not well understood. This book provides a
wealth of information for those who are already in the field, and for others who
aspire to join them and make their contributions to shape the future advances in
research on epigenomics.
Azim Surani Ph.D. F.Med.Sci. F.R.S.
Marshall-Walton Professor and Head of Wellcome Laboratories
Wellcome Trust Cancer Research UK Gurdon Institute
University of Cambridge
xxvi Foreword
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Preface
It is not enough to discover and prove a useful truth previously unknown, but it is necessary alsoto be able to propagate it and get it recognized.
Jean-Baptiste Lamarck, French naturalist (1744–1829) Philosophie Zoologique (1809),vol. 2, p. 450
Epigenetics: a Greek termmeaning “above and beyond the gene.” The late Conrad
Waddington, the last Renaissance evolutionary biologist from the University of
Edinburgh, Scotland, coined the word epigenetics in the 1940s for a phenomenon:
“that phenotypes arises from genotype through programmed change.” Taking the past
two decades of work on epigenetics into consideration Adrian Bird of the
University of Edinburgh provided a unifying definition of epigenetics as: “the
structural adaptation of chromosomal regions so as to register, signal or perpetuate
altered activity states.” According to Andrew Feinberg of the Johns Hopkins
University, Baltimore, USA, the modern definition of epigenetics is “information
heritable during cell division other than the DNA sequence itself.” Epigenetics is one of
the fundamentalmechanisms that is involved in embryo development and differ-
entiation of cell types. One of the most exciting frontiers in both epigenetics and
genomics (genome sciences) is the new field of epigenomics which can be defined
as: “the study of epigenetic marks in a given cell type using genomics technologies.” This
new discipline promises novel insights into the genome because of its potential to
detect quantitative alterations, multiplex modifications, and regulatory sequen-
ces outside of genes.
Epigenomics: From Chromatin Biology to Therapeutics is mainly intended for read-
ers in the genomics, biotechnology, and molecular medicine fields. There are
quite a number of books already available covering epigenetics/epigenomics.1
For example, the book by Jablonka and Lamb (1995) emphasizes the importance
of “epigenetic inheritance and evolution” specially focusing on the Lamarckian
approach, whereas the book by Allis et al. (2007) nicely provides the principles of
epigenetics. Three recent books, by Esteller (2009), Ferguson-Smith et al. (2009),
and Tost (2010), have covered the importance of DNA methylation in
1 Jablonka, E., and Lamb, M. (1995) Epigenetic Inheritance and Evolution: The LamarckianDimension, New York: Oxford University Press; Allis, C. D., et al. (2007) Epigenetics, ColdSpring Harbor Laboratory Press; Esteller, M. (2009) Epigenetics in Biology and Medicine, BocaRaton, FL: CRC Press; Ferguson-Smith, A.C., et al. (2009) Epigenomics, New York: Springer;Tost, J. (2010) DNA Methylation: Methods and Protocols, New York: Springer. xxvii
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development and cancer. The present book differs, in that it is the first text
completely devoted to the new field of epigenomics covering the basic biological,
biochemical, molecular, and genomics aspects of epigenetics and their impor-
tance in health and disease biology. This book focuses on the history, biology, and
biochemistry of chromatin, epigenomic imprinting, assay technology platforms,
and cancer biology. Particularly, this book highlights the importance of epi-
genomics in variation (includes polymorphism), epidemiology (environment
and nutrition), and neurodegenerative diseases. The goal is to have this book
serve as a reference for graduate students, post-doctoral researchers, and teachers
and as an explanatory analysis for executives and scientists in biotechnology and
pharmaceutical companies. Our hope is that this volume will serve as a prologue
to the field for both new comers and those already active in the field. This book is
differentiated from others due to its careful integration of relevant emerging
chromatin immunoprecipitation (ChIP) and sequencing platforms that have
been continuously used today by various scientists to decipher the code of “epi-
epigenomes” in normal and diseased cells. We carefully chose the chapters writ-
ten by experts in the field from academia and industry and made appropriate
sections to maintain the theme expressed in the subtitle of this book: From
Chromatin Biology to Therapeutics.
Three epigenetic systems, i.e., X-chromosome inactivation, genetic imprinting,
and epigenetic modifications, are the building blocks of the field of epigenomics.
X-chromosome inactivation is the fundamental and common type of epigenetic
marking that occurs during embryogenesis in female mammals. This mechanism
was experimentally demonstrated in 1961 by Mary Lyon of the Medical Research
Council’s Mammalian Genetics Unit in Oxfordshire, UK; thus it is referred to as
lyonization. In 1975 Robin Holliday of the Medical Research Council’s National
Institute for Medical Research, London, UK, and Arthur Riggs of the Beckman
Research Institute of the City of Hope, Duarte, USA independently proposed a
molecular model for somatic cell inheritance emphasizing that DNA methylation
could be an important mechanism for the control of gene expression in higher
organisms.
A second form of epigenetic inheritance is genomic imprinting, in which
“stamping” of the genetic information occurs according to whether it is inherited
from the mother or the father. This has been independently shown by Azim
Surani of the University of Cambridge, UK, Bruce Cattanach of the Medical
Research Council’s Mammalian Genetics Unit, and Davor Solter of the Max-
Planck Institute for Immunobiology, Freiburg, Germany. Genomic imprinting is
the prime example of “transgenerational epigenetic inheritance” because the
imprint that is established in the germ-line of a parent is passed on to the offspring
where it is “read” in the next generation. This discovery was a harbinger of the
exciting (and currently flourishing) research area of epigenetics and epigenomics.
DNA methylation, histone modifications, and nucleosome positioning are the
important parts of the machinery of the epigenome. Each part involves a battery
of enzymes and protein complexes, including methyltransferases, acetyl trans-
ferases, histone deactylases, and several signaling molecules. The biochemistry
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of these modifications is the subject of this book. Understanding chromatin
biology and the dynamics of the epigenome in development, aging, and disease
states will help us to better understand the “histone code,” and to developmodels
for screening environmental compounds and chemicals.
It is increasingly being recognized that epigenetic modifications are critical to
disease pathogenesis. The first example of a human disease with an epigenetic
mechanism was shown in cancer by Andrew Feinberg and Bert Vogelstein of the
Johns Hopkins University, in 1983, but today it can be seen in several human
diseases such as cardiovascular, diabetes, neurodegenerative and inflammatory
diseases.Muchof the recent growth in the field can be attributed to the technology-
enabled ability to survey epigenetic modifications on a genome-wide scale. Large-
scale epigenomicmapping projects have the potential to provide global, integrated
views of different cellular states. Modern biomedical science is finally bringing
together the intellectual forces of international academic researchers, industry
scientists, and clinicians to map all themethylomes and/or epigenomes. Such collab-
orations have been initiated, and are relevant for the emerging science of epige-
netics and epigenomics.
Epidemiology is the study of factors affecting the health and illness of human
populations. Some of those factors include nutrition (diet), chemical exposure,
behavior, and environment. It turns out that nutrition affects the way our genetic
code is expressed: this was shown in the 1980s by Lars Olov Bygren of Umeå
University, Sweden by analyzing agricultural records of the children growing up
in Norrbotten in the nineteenth century. Effects of nurture (environment) on a
species’ nature (genes) were not supposed to happen so quickly and should take
place over many generations and throughmillions of years of natural selection as
proposed by evolutionary biologist Charles Darwin in his famous On the Origin of
Species. But after all that, now Bygren and other scientists have amassed historical
evidence as a trump card to play against Darwin! The present environmental/
epigenetic inheritance principles are similar to those proposed earlier by evolution-
ist Jean-Baptiste Lamarck (1744–1829), who believed that the environment plays
an important role in an organism’s acquisition of evolutionary characteristics.
Recent neo-Lamarckian researchers now believe that the environment plays a key
role in a species acquiring inherited characteristics that drive variation and evo-
lution. Decades later, many of Lamarck’s theories are now being shown to be
surprisingly correct.
Randy Jirtle of Duke University, Research Triangle, North Carolina, USA has
shown for the first time that chemical exposure alters the physical characteristics
of an organism by reducing the DNA methylation, and affects the next genera-
tions. Behavior (childhood abuse and suicidal nature) affects gene expression and
passes to the next generation, as shown recently by Gustavo Turecki, a medical
scientist from McGill University, Montreal, Canada. Bruno Reversade, a develop-
mental biologist at Singapore’s Institute of Medical Biology, is studying the effect
of environment and genetic variant(s) on the biology of monozygous twins.
However, no common allele or environmental factors or epigenetic factors have
yet been identified behind the twinning process. In conclusion, it is now quite
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evident that chemical exposures and nutrition play a significant role at the
epigenetic level and affect gene expression and regulation.
Many people have contributed to making our involvement in this project
possible. We thank our teachers for their excellent teaching, guidance, and men-
torship, which helped us to bring about this educational enterprise. We are
extremely grateful to all of the contributors to this book, without whose commit-
ment this book would not have been possible. Many people have had a hand in
the preparation of this book. Each chapter has been passed back and forth
between the authors for criticism and revision; hence each chapter represents a
joint composition. We thank our readers, who have made our hours putting
together this volume worthwhile. We are indebted to the staff of the Cambridge
University Press, and in particular Katrina Halliday for her generosity and effi-
ciency throughout the editing of this book; she truly understands the urgency and
need of this volume. We also extend our appreciation to Hans Zauner for his
excellent cooperation during the development of this volume. We thank English
molecular biologist Robin Holliday (presently in Australia) and Swedish epidemi-
ologist Lars Olov Bygren, men of encyclopedic interests and knowledge, for their
understanding and support in writing on historical and epidemiological aspects
respectively in this book. We want to thank Professor Azim Surani, an English
developmental molecular biologist, and one of the pioneers in the field of epi-
genetics, for his kindness in writing the Foreword to this book. Last, but not least,
we thank Shyamala Appasani for her understanding and cooperation during the
development of this interesting volume.
This book is the second joint project of father and son. A portion of the royalties
will be contributed to the Dr. Appasani Foundation (a non-profit organization
devoted to bringing social change through the education of youth in developing
nations) and MINDS Foundation (Mental Illness and Neurological Diseases),
which is committed to taking a grassroots approach in eliminating stigma and
providing educational, financial, medical, and moral support for patients suffer-
ing from mental illness in developing countries.
Krishnarao Appasani
Raghu K. Appasani
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