Epigenomics From Chromatin Biology to Therapeuticsassets.cambridge.org/97811070/03828/frontmatter/... · Epigenomics From Chromatin Biology to Therapeutics Understanding mechanisms

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.

www.cambridge.org© in this web service Cambridge University Press

Cambridge University Press978-1-107-00382-8 - Epigenomics: From Chromatin Biology to TherapeuticsEdited by Krishnarao AppasaniFrontmatterMore information

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Epigenomics

FROM CHROMATIN BIOLOGY TO THERAPEUTICS

Edited by

Krishnarao AppasaniGeneExpression Systems, Inc.

Foreword by

Azim SuraniUniversity of Cambridge






CAMBR IDGE UN IV E R S I T Y P R E S S

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Cambridge University Press

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Published in the United States of America by Cambridge University Press, New York

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© 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.






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











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






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






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






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






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






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


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






Beech Hill Road,

Sheffield, S10 2RX, UK

Jeffrey D. Falk

Aviva Systems Biology

5754 Pacific Center Blvd., Suite 201


Presently at: RiboMed Biotechnologies, Inc.

2736 Loker Avenue West, Suite C


Jian-Bing Fan

Illumina, Inc.



Joseph M. Fernandez

Active Motif, Inc.



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”


via Irnerio, 48


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






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


Laboratory of Cellular and Molecular Engineering

via Venezia, 52

Cesena, I-43027, Italy

and

Dipartimento di Biochimica “G. Moruzzi”

via Irnerio, 48


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



via Irnerio, 48


Kevin L. Gunderson

Illumina, Inc.



xiv List of contributors






Victoria (Fatemeh) G. Haghighi

Columbia University Department of Psychiatry

New York State Psychiatric Institute

1051 Riverside Drive, Box 42


Xu Han



Yantian District


Yong-Mahn Han

Department of Biological Sciences

KAIST

335 Gwahangno, Yuseong

Daejeon 305-701, Korea

Howard C. Hang





Aditi Hazra

Harvard School of Public Health

Channing Laboratory

181 Longwood Avenue, Room 355


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


Robin Holliday

Australian Academy of Sciences

12 Roma Court

West Pennant Hills, NSW 2125, Australia

List of contributors xv






Dorothee Honsel

QIAGEN GmbH

QIAGEN Strasse 1


Mary A. Jelinek

Active Motif, Inc.



Guanyu Ji



Yantian District


Yan Jiang

Brudnick Neuropsychiatric Research Institute


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



Richard Kroon

QIAGEN GmbH

QIAGEN Strasse 1


xvi List of contributors






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


KAIST



Konstantin Lepikhov

Saarland University

FR 8.3 Biosciences

Laboratory of EpiGenetics


Postbox 151150


Andrea Linnemann-Florl

QIAGEN GmbH

QIAGEN Strasse 1


Dirk Loeffert

QIAGEN GmbH

QIAGEN Strasse 1


Dylan Maixner






List of contributors xvii






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


D.V. Mohankrishna




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



Rituparna Mukhopadhyay

Department of Cell Biology

Albert Einstein College of Medicine

1300 Morris Park Avenue, Ullmann 903

Bronx, NY 10461, USA

Claudio Muscari



via Irnerio, 48


Takashi Nagano

Nuclear Dynamics Programme

The Babraham Institute

Babraham Research Campus

Cambridge, CB22 3AT, UK

xviii List of contributors






Frank Narz

QIAGEN GmbH

QIAGEN Strasse 1


Shuji Ogino

Department of Pathology

Brigham and Women’s Hospital, Harvard Medical School

75 Francis Street


Carlo M. Oranges

School of Plastic Surgery



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



via Irnerio, 48

Bologna , I-40126, Italy

Ralf Peist

QIAGEN GmbH

QIAGEN Strasse 1


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

List of contributors xix






Andrey Poleshko

Fox Chase Cancer Center

333 Cottman Avenue


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


Ana Sanz

Active Motif, Inc.



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


Kornel Schuebel






B.Ruthrotha Selvi




Karnataka, India

xx List of contributors






Hogyu Seo


KAIST



Natalia Shalginskikh

Fox Chase Cancer Center

333 Cottman Avenue


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


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


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

List of contributors xxi






Gustavo Turecki

McGill Group for Suicide Studies


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


Postbox 151150


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


Postbox 151150


xxii List of contributors






Honglong Wu



Yantian District


Yurong Xin





Zhixiang Yan



Yantian District


Yu-Ying Yang





Mingzhi Ye



Yantian District


Kyoko Yokomori


School of Medicine

University of California–Irvine


Sephorah Zaman





Weihua Zeng


School of Medicine

List of contributors xxiii






University of California–Irvine


Gerald Zon

Formerly at: Life Technologies

850 Lincoln Center Drive

Foster City, CA 94404, USA

xxiv List of contributors






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

xxv






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






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






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

xxviii Preface






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

Preface xxix






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

xxx Preface






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