Personalized Epigenetics

573 Pages·2015·8.75 MB·English

by  Trygve Tollefsbol

PERSONALIZED
EPIGENETICS
Trygve O. TOllefsbOl

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Contributors
Vanessa Aguiar-Pulido School of Computing & Information Sciences, Florida
International University, Miami, FL, USA; Department of Information &
Communication Technologies, University of A Coruña, A Coruña, Spain
Alexandre F. Aissa Department of Clinical Analyses, Toxicology and Food
Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São
Paulo (USP), Ribeirão Preto, São Paulo, Brazil
Seena K. Ajit Department of Pharmacology & Physiology, Drexel University
College of Medicine, Philadelphia, PA, USA
Lusânia M.G. Antunes Department of Clinical Analyses, Toxicology and Food
Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São
Paulo (USP), Ribeirão Preto, São Paulo, Brazil
Elisabeth B. Binder Max Planck Institute of Psychiatry, Translational Research,
Munich, Germany
Christopher Chang Division of Rheumatology, Allergy and Clinical Immunol-
ogy, University of California at Davis, CA, USA
Samit Chattopadhyay National Centre for Cell Science, Pune University
Campus, Ganeshkhind, Pune, India
Arpankumar Choksi National Centre for Cell Science, Pune University Campus,
Ganeshkhind, Pune, India
Fabio Coppedè Department of Translational Research and New Technologies in
Medicine and Surgery, University of Pisa, Pisa, Italy
Jose M. Eirin-Lopez Department of Biological Sciences, Florida International
University, North Miami, FL, USA
Ammad A. Farooqi Laboratory for Translational Oncology and Personalized
Medicine, Rashid Latif Medical College, Lahore, Pakistan
Domniki Fragou Laboratory of Forensic Medicine and Toxicology, School of
Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
Rebecca C. Fry Department of Environmental Sciences and Engineering,
University of North Carolina, Chapel Hill, NC, USA; Curriculum in Toxicology,
School of Medicine, University of North Carolina, Chapel Hill, NC, USA
Gunnar H. Heine Department of Internal Medicine IV, Nephrology and
Hypertension, Saarland University Medical Center, Homburg, Germany
Anke Hoffmann Max Planck Institute of Psychiatry, Translational Research,
Munich, Germany
Muhammad Ismail IBGE, Islamabad, Pakistan
Leda Kovatsi Laboratory of Forensic Medicine and Toxicology, School of
Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
xiii
vix CONTRIBUTORS
Anders M. Lindroth Graduate School of Cancer Science and Policy, National
Cancer Center, Goyang-si, Republic of Korea
Ying Liu Department of Dermatology, Hunan Key Laboratory of Medical
Epigenomics, Second Xiangya Hospital, Central South University, Hunan, China
Angela Lopomo Department of Translational Research and New Technologies
in Medicine and Surgery, University of Pisa, Pisa, Italy; Doctoral School in
Genetics, Oncology, and Clinical Medicine, University of Siena, Siena, Italy
Kenneth Lundstrom PanTherapeutics, Lutry, Switzerland
Qianjin Lu Department of Dermatology, Hunan Key Laboratory of Medical
Epigenomics, Second Xiangya Hospital, Central South University, Hunan,
China
Emily Machiela Laboratory of Aging and Neurodegenerative Disease, Van
Andel Research Institute, Grand Rapids, MI, USA
Lucia Migliore Department of Translational Research and New Technologies in
Medicine and Surgery, University of Pisa, Pisa, Italy
Giri Narasimhan School of Computing & Information Sciences, Florida
International University, Miami, FL, USA
Monica D. Nye Department of Environmental Sciences and Engineering,
University of North Carolina, Chapel Hill, NC, USA
Joo H. Park Department of Nutritional Science and Food Management, Ewha
Womans University, Seoul, Republic of Korea
Yoon J. Park Department of Nutritional Science and Food Management, Ewha
Womans University, Seoul, Republic of Korea
Sonal Patel National Centre for Cell Science, Pune University Campus,
Ganeshkhind, Pune, India
Jacob Peedicayil Department of Pharmacology and Clinical Pharmacology,
Christian Medical College, Vellore, India
Javier Pereira Department of Information & Communication Technologies,
University of A Coruña, A Coruña, Spain
Anthony Popkie Laboratory of Cancer Epigenomics, Van Andel Research
Institute, Grand Rapids, MI, USA
Muhammad Z. Qureshi Department of Chemistry, GCU, Lahore, Pakistan
Nicole C. Riddle Department of Biology, The University of Alabama at
Birmingham, Birmingham, AL, USA
Lorenzo F. Sempere Laboratory of MicroRNA Diagnostics and Therapeutics,
Van Andel Research Institute, Grand Rapids, MI, USA
Dietmar Spengler Max Planck Institute of Psychiatry, Translational Research,
Munich, Germany
Victoria Suarez-Ulloa Department of Biological Sciences, Florida International
University, North Miami, FL, USA
D. Syndercombe Court Faculty of Biological Sciences and Medicine, King’s
College London, London, UK
CONTRIBUTORS vx
Trygve O. Tollefsbol Department of Biology, University of Alabama at Birming-
ham, Birmingham, AL, USA; Comprehensive Cancer Center, University of
Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Center for
Healthy Aging, University of Alabama at Birmingham, Birmingham, AL, USA;
Nutrition Obesity Research Center, University of Alabama at Birmingham, Bir-
mingham, AL, USA; Comprehensive Diabetes Center, University of Alabama
at Birmingham, Birmingham, AL, USA
Athina Vidaki Faculty of Biological Sciences and Medicine, King’s College
London, London, UK
Louis P. Watanabe Department of Biology, The University of Alabama at
Birmingham, Birmingham, AL, USA
Hehuang Xie Department of Biological Sciences, Virginia Bioinformatics
Institute, Virginia Tech, Blacksburg, VA, USA
Yeongran Yoo Department of Nutritional Science and Food Management, Ewha
Womans University, Seoul, Republic of Korea
Andrew E. Yosim Department of Environmental Sciences and Engineering,
University of North Carolina, Chapel Hill, NC, USA
Adam M. Zawada Department of Internal Medicine IV, Nephrology and
Hypertension, Saarland University Medical Center, Homburg, Germany
Peng Zhang Department of Dermatology, Hunan Key Laboratory of Medical
Epigenomics, Second Xiangya Hospital, Central South University, Hunan,
China
Christoph A. Zimmermann Max Planck Institute of Psychiatry, Translational
Research, Munich, Germany
Preface
It is now apparent that epigenetics is a central component of medicine.
In light of that fact, future diagnostic, prognostic, and therapeutic advances
will almost certainly increasingly rely on personalized epigenetics for the
optimal management of many, if not most, health-related conditions.
Personalized epigenetics notably stands out in that the emphasis is on
the translatability of epigenetics to health management of individuals who
have unique variations in their epigenetic signatures that can guide dis-
order or disease prevention or therapy. The goal of this book on personal-
ized epigenetics is to provide a comprehensive analysis of interindividual
variability of epigenetic markers of human disease and to illuminate the
bench to bedside advances that are readily advancing in this field. More
specifically, the purpose of this book focusing on personalized epigenetics
is to facilitate understanding of the application of medical prevention
and therapy based in part on the unique health and disease susceptible
epigenetic profile of each individual.
This book is intended for those with interests ranging from basic
molecular biology to clinical therapy and who have an interest in person-
alized medicine.
Trygve O. Tollefsbol
xvii
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O U T L I N E
.1 nI trodcu tion 4
.2 Epigenetic V ariations aom ng nI diiv dau ls 4
.3 iB oinof ram tics o f Personalized Epigenetics 6
.4 iD agnostic and Prognostic Epigenetic pA proaceh s to Personalized
eM dicine 6
.5 Eniv ronem ntal Personalized Epigenetics 8
.6 Pah ram colog y and rD gu eD ev lopem nt o f Personalized Epigenetics 8
.7 Personalized Epigenetics o f iD sorders and iD sease aM nageem nt 9
.8 ahC llenges and tuF ru e iD rections 1
.9 oC nclsu ion 1
eR ef rences 21
Personalized Epigenetics 3
http://dx.doi.org/10.1016/B978-0-12-420135-4.00001-2 © 2015 Elsevier Inc. All rights reserved.
4 1. EPIGENETICS OF PERSONALIZED MEDICINE
1. INTRODCU TION
While each species, cell, and system has a characteristic epigenetic pro-
file, individuals also have an epigenetic profile that forms their unique
epigenome. Epigenetic aberrations are known to play a key role in many
human diseases, and the purpose of personalized epigenetics is to base
medical prevention and therapeutics as well as diagnostics and prognos-
tics on the distinctive health and disease susceptibility profile of each indi-
vidual. In fact, interindividual differences in the epigenome are the basis
of personalized epigenetics and these can manifest through epigenetic
signatures that are characteristic of each individual. DNA methylation, for
example, varies between individuals [1–2] as do the many different forms
of epigenetic histone modifications [3–4]. In addition, noncoding RNA
profiles are also variable from person to person [5–6]. These variations in
epigenetic expression will undoubtedly become increasingly important as
the potential for personalized epigenetics in medicine continues to grow.
Personalized epigenetics can serve as a guide not only for the therapy
of epigenetic-based diseases, but also for many other aspects of medicine.
Epigenetic biomarkers comprising epigenomic signatures unique to each
individual have increasingly been shown to provide not only valuable
information with respect to the diagnosis of disorders and diseases, but
also prognostic information pertaining to the likely progression of diseases
such as cancer [7–8]. There are also many applications of personalized epi-
genetics in forensics and in toxicology. Many toxic compounds leave dis-
tinct epigenomic signatures that could have significant utility in terms of
diagnosing toxicity as well as treatment of patients that have been exposed
to toxins [9–10]. Similar concepts apply to environmental contaminants
[11–12] and nutrients [13–14] that also have an impact on the epigenome.
Equally exciting is the prospect of application of personalized epi-
genetics to the many disorders and diseases that have epigenetic aber-
rations as a component of their etiology or pathogenesis. For example,
epigenetic alterations have been shown in a number of studies to be
important in chronic pain, and studies are emerging that may lead to
personalized management of pain based on the distinct epigenomic pro-
file of the individual patient [15–16]. Approaches to patient management
through personalized epigenetics are also rapidly developing for many
other medical conditions such as obesity, cancer, autoimmune disorders,
and cardiovascular diseases.
.2 EPIGENETIC V ARIATIONS AMONG INDIIV DAU LS
One of the most important components of the collective epigenetic
changes that occur in cells and tissues is DNA methylation. The role of
DNA methylation in modulating gene expression has been known for
I. OEV RIV E W
2. EPIgENETIC VARIATIONs AMONg INdIVIdUALs 5
quite some time, although it has been more recently appreciated that it can
vary considerably between individuals within a species. As Watanabe and
Riddle explain in Chapter 2, the variation in DNA methylation between
individuals is a common feature ranging from plants to humans. There
are a number of possible causes for extensive variance of DNA methyla-
tion among individuals, including gender, health status, age, and envi-
ronmental exposures, as well as many other factors. The heterogeneity of
DNA methylation patterns within individuals is of particular interest to
those focused on personalized medicine. For example, interindividual dif-
ferences in DNA methylation have considerable potential as a biomarker
for a number of diseases as well as a means to guide therapy for diseases
such as cancer. In fact, the optimal drug dosage that is administered to
individual patients could be monitored through changes in the patient’s
DNA methylation profile, which serves as a classic example of the util-
ity of knowledge of personalized epigenetics as applied to medicine, as
reviewed in Chapter 2.
There are many different types of histone modifications that can modu-
late epigenetic gene expression of an organism and these modifications are
also subject to interindividual variation. The importance of individual het-
erogeneity of histone modifications as well as techniques such as mapping
of DNase I-hypersensitive sites and formaldehyde-assisted isolation of
regulatory elements (FAIRE) and chromatin immunoprecipitation (ChIP),
as well as their genomic counterparts (DNase-seq, FAIRE-seq, and ChIP-
seqA), is highlighted in Chapter 3. Especially fascinating is the prospect
of the potential use of induced pluripotent stem cells for elucidating chro-
matin modifications and transcription differences in healthy and disease
states as a “bottom-up” approach (Chapter 3) to advance our knowledge
of chromatin heterogeneity between individuals and the potential applica-
tion of this knowledge to personalized medicine.
Noncoding RNA (ncRNA) variations have great importance to
personalized epigenetics since ncRNAs such as microRNAs (miRNAs),
trinucleotide repeats, and long noncoding RNAs not only regulate epigen-
etic processes, but are in turn regulated by epigenetic processes as well.
Variation in ncRNA sequences can modulate not only RNA stability, but
also its processing, which can affect the regulatory capacity of ncRNAs. As
delineated in Chapter 4, these differences in ncRNAs between individuals
can lead to major epigenetic changes in disease processes and may also
have utility as biomarkers of various diseases. For example, there is some
evidence that miRNA expression signatures may distinguish Alzheimer’s
disease and Parkinson’s disease from normal controls (Chapter 4). More-
over, variations of ncRNAs between individuals could be employed for
personalized medical therapy through monitoring of drug responses.
Despite great excitement in the potential uses of interindividual
epigenetic variations in personalized medicine, there are some limita-
tions that must be overcome. For instance, there can be challenges in
I. OVERVIEW
6 1. EPIGENETICS OF PERSONALIZED MEDICINE
detecting true epi-mutations, and epigenetic signatures vary not only among
individuals, but also between the various cell types within individuals
(Chapter 5). There can also be complications with respect to allele-specific
or asymmetric DNA methylation changes that can add to the complexity
of interpretations of epigenetic differences between individuals. Neverthe-
less, it is apparent that interindividual differences in epigenetic processes
such as DNA methylation is substantial and the collective pattern differ-
ences in response to medical interventions have considerable promise in
leading to many advances in medical diagnosis, prognosis, and therapy.
.3 IB OINFO RMATICS OF PERSONALIZED
EPIGENETICS
Although the heterogeneity of epigenetic events presents a challenge
in monitoring reliable changes in epigenetic patterns between individuals
and in response to medical interventions, computational epigenetics pro-
vides many solutions to this challenge. Chapter 6 reviews the data types
most often used in epigenetic studies and their use in medicine. Compu-
tational approaches to DNA methylation patterns, histone modifications,
and ncRNAs as well as quantitative protein analyses are greatly enhancing
the ability to identify specific differences in epigenetic profiles between
individuals that can be readily applied to personalized medicine. Technol-
ogies such as grid computing, which involves coupling of networked and
geographically dispersed computers that, in combination, will be able to
perform the requisite computational tasks that will enable more accurate
analyses of variations in epigenetic signatures, are discussed.
.4 DIAGNOSTIC AND PROGNOSTIC EPIGENETIC
APPROACEH S TO PERSONALIZED MEDICINE
The further development of epigenetic biomarkers has considerable
potential to significantly advance personalized medicine. Epigenetic sig-
natures, for example, unique epigenetic features of DNA methylation or
ncRNA, may be applied not only to diagnostic aspects of personalized
care, but also to prognosticating the progression of diseases (Chapter 7).
Moreover, epigenetic biomarkers are being developed to monitor the
most efficacious approaches to therapy. The development of epigenetic
biomarkers has been most readily apparent in the field of tumor biol-
ogy. These biomarkers provide both diagnostic and prognostic informa-
tion, since different epigenetic markers may be present at various stages
of carcinogenesis, thereby conferring predictive potential of disease out-
come in different individuals. Changes in the epigenetic signature during
I. OEV RIV E W