Advances in Experimental Medicine and Biology 1253

Christopher ChangQianjin Lu   Editors

Epigenetics in Allergy and Autoimmunity

Advances in Experimental Medicine and Biology

Volume 1253

Series Editors

Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine,CNRS and University of Bordeaux UMR 5287, Pessac Cedex, France

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Heinfried H. Radeke, Institute of Pharmacology & Toxicology, Clinic of theGoethe University Frankfurt Main, Frankfurt am Main, Hessen, Germany

Nima Rezaei, Research Center for Immunodeficiencies, Children’s Medical Center,Tehran University of Medical Sciences, Tehran, Iran

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Christopher Chang • Qianjin LuEditors

Epigenetics in Allergyand Autoimmunity

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EditorsChristopher ChangDivision of Pediatric Immunologyand AllergyJoe DiMaggio Children’s HospitalHollywood, FL, USA

Division of Rheumatology, Allergyand Clinical ImmunologyUniversity of California DavisDavis, CA, USA

Qianjin LuDepartment of Dermatology, Hunan KeyLaboratory of Medical EpigenomicsSecond Xiangya Hospital, Central SouthUniversityChangsha, Hunan, China

ISSN 0065-2598 ISSN 2214-8019 (electronic)Advances in Experimental Medicine and BiologyISBN 978-981-15-3448-5 ISBN 978-981-15-3449-2 (eBook)https://doi.org/10.1007/978-981-15-3449-2

© Springer Nature Singapore Pte Ltd. 2020This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or partof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmissionor information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilarmethodology now known or hereafter developed.The use of general descriptive names, registered names, trademarks, service marks, etc. in thispublication does not imply, even in the absence of a specific statement, that such names are exempt fromthe relevant protective laws and regulations and therefore free for general use.The publisher, the authors and the editors are safe to assume that the advice and information in thisbook are believed to be true and accurate at the date of publication. Neither the publisher nor theauthors or the editors give a warranty, expressed or implied, with respect to the material containedherein or for any errors or omissions that may have been made. The publisher remains neutral with regardto jurisdictional claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd.The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,Singapore

This book is dedicated to all patients withallergic and autoimmune diseases, in thehope that one day there will not just betreatments but cures.

Preface

As personalized medicine becomes more and more of a mainstream term, there isno consensus on how to achieve this lofty goal. The dream of being able toprecisely identify patients who will respond optimally to a given treatment has notyet been realized, but epigenetics, the study of how genes are turned on and off bychanges not in DNA sequence but in alterations of various elements of chromatin,including nucleotides within the DNA and proteins which regulate expression thatare in close physical contact with DNA, offers great promise in ultimately achievingthis goal. The study of the impact of epigenetics in health and disease originatedonly about 40 or so years ago and began in the oncology arena, but then quicklyprogressed to include autoimmune diseases. Our understanding of the role of epi-genetics has been facilitated by large populations studies and by the existence ofdiscordant twins, in other words, monozygotic twins who generally have identicalDNA but still manage to manifest changes in disease presentation. This work isintended to cover the topics relating to epigenetics in allergic diseases andautoimmune diseases. The aim is to provide a comprehensive source of informationfor scientists, clinicians, fellows, residents and students who are interested incutting-edge developments in epigenetic research designed to elucidate mechanismsof disease and the fulfilment of that promise of personalized medicine.

My colleague and co-editor, Professor Qianjin Lu, is the Head of the Hunan KeyLaboratory for Epigenetics Research and has published numerous papers on the roleof epigenetics in dermatology and rheumatology. I have been privileged to haveshared in the publication of some of these articles. Professor Lu and I have selectedthe world’s foremost experts in epigenetics in their research field to cover diseasesranging from allergic rhinitis and asthma to primary biliary cirrhosis and multiplesclerosis. We hope that this book will help the reader understand the importance ofthis research to the future of mankind, not only in preventing and treating diseases,but also in the appreciation of how good health can be maintained.

This project was first conceived three years ago, at the 2017 InternationalSymposium of Autoimmunity in Beijing, China. Professor Lu and I would like tothank Peng Zhang, our tireless publications liaison at Springer who first approachedus with the proposal, and Professor Haijing Wu, who co-authored the chapters on

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food allergies and systemic lupus erythematosus and also helped with proofing andmany of the administrative tasks one faces when editing a scientific work. Wewould like to extend our thanks to the authors of each of the individual chapters, fortheir willingness to devote large amounts of time to share their expertise with us.We would also like to thank our families, who endured many solitary hours withoutus as we retreated to our workspaces to continue our own work in bringing thisbook into production. It has been a challenging but rewarding task.

Finally, we hope that an appreciation of the importance of epigenetics in healthand disease will spawn further research in this area and the book will provide alaunching pad for young investigators interested in developing a career inepigenetics.

Hollywood, FL, USAMay 2020

Christopher Chang

viii Preface

Contents

Part I Introduction

1 Epigenetics in Health and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 3Lian Zhang, Qianjin Lu, and Christopher Chang

2 The Development of Epigenetics in the Study of DiseasePathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57Matlock A. Jeffries

3 Epigenetic Methods and Twin Studies . . . . . . . . . . . . . . . . . . . . . . 95Angela Ceribelli and Carlo Selmi

Part II Allergic Diseases

4 The Role of Genetics, the Environment, and Epigeneticsin Atopic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107Zhanglei Mu and Jianzhong Zhang

5 The Epigenetics of Food Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Christopher Chang, Haijing Wu, and Qianjin Lu

6 Epigenetics and the Environment in Airway Disease:Asthma and Allergic Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Andrew Long, Bryan Bunning, Vanitha Sampath,Rosemarie H. DeKruyff, and Kari C. Nadeau

Part III Autoimmune Diseases

7 The Epigenetics of Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . 185Haijing Wu, Christopher Chang, and Qianjin Lu

8 Epigenetics of Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209Shuai Shao and Johann E. Gudjonsson

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9 The Role of Epigenetics in Type 1 Diabetes . . . . . . . . . . . . . . . . . . 223Zhiguo Xie, Christopher Chang, Gan Huang, and Zhiguang Zhou

10 Epigenetics of Primary Biliary Cholangitis . . . . . . . . . . . . . . . . . . . 259Yikang Li, Ruqi Tang, and Xiong Ma

11 Epigenetics in Primary Sjögren’s Syndrome . . . . . . . . . . . . . . . . . . 285Anne Bordron, Valérie Devauchelle-Pensec, Christelle Le Dantec,Arthur Capdeville, Wesley H. Brooks, and Yves Renaudineau

12 Epigenetics in Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 309Vera Sau-Fong Chan

13 The Epigenetic Regulation of Scleroderma and Its ClinicalApplication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375Yangyang Luo and Rong Xiao

x Contents

Editors and Contributors

About the Editors

Dr. Christopher Chang is a Clinical Professor of Medicine in the Division ofRheumatology, Allergy and Clinical Immunology at the University of California,Davis. He is Professor of Pediatrics at Florida International University and FloridaAtlantic University and is Medical Director of Pediatric Immunology, Allergy andRheumatology at Joe DiMaggio Children’s Hospital, Memorial Health Systems. Heis also a visiting Professor at Xiangya School of Medicine, Central SouthUniversity in Changsha, Hunan, China. Dr. Chang is a fellow of the AmericanAcademy of Allergy, Asthma and Immunology and the American College ofAllergy, Asthma and Immunology, and a member of the Clinical ImmunologySociety and the American Association of Immunologists. His interests are mainlyfocused on epigenetic regulation in allergy and autoimmune diseases. He haspublished more than 20 articles in this field. He is also Editor-in-Chief of theJournal of Evidence-Based Integrative Medicine, Co-Editor of the Journal ofTranslational Autoimmunity and Associate Editor of Clinical Reviews in Allergyand Immunology.

Dr. Qianjin Lu is currently Professor and Director of the Institute of Dermatologyat the Central South University. He is also Director of the Hunan Key Laboratory ofMedical Epigenomics, and current President of the Chinese Society ofDermatology. Professor Lu has accumulated rich clinical experience in dermatol-ogy, especially in the areas of lupus and psoriasis. He has conducted research inepigenetic and autoimmunity for more than twenty years and he is especiallyinterested in epigenetic regulation in the pathogenesis of systemic lupus erythe-matosus and psoriasis. Professor Lu has published 200 papers in high impactjournals including Lancet, JAMA, Blood, J Clin Invest, Ann Rheum Dis and JImmunol, etc. In recent years, Professor Lu was honored with several awards suchas Second Prize of the National Scientific and Technological Progress Award, First

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Prize of the Natural Scientific Research Award of Hunan Province, First Prize of theScientific and Technological Progress Award of Hunan Province and OutstandingMedical Scientist of China.

Contributors

Anne Bordron INSERM U1227, «Lymphocyte B et autoimmunité», Labex Igo“Immunotherapy Graft, Oncology”, Réseau épigénétique du cancéropole GrandOuest, Université de Brest, Brest, France

Wesley H. Brooks Department of Chemistry, University of South Florida, Tampa,FL, USA

Bryan Bunning Division of Pulmonary and Critical Care Medicine, Departmentof Medicine, Sean N. Parker Center for Allergy and Asthma Research at StanfordUniversity, Stanford, CA, USA

Arthur Capdeville INSERM U1227, «Lymphocyte B et autoimmunité», LabexIgo “Immunotherapy Graft, Oncology”, Réseau épigénétique du cancéropole GrandOuest, Université de Brest, Brest, France

Angela Ceribelli Humanitas Clinical and Research Center—IRCCS, Rozzano,Milan, Italy

Vera Sau-Fong Chan Department of Medicine, Li Ka Shing Faculty of Medicine,The University of Hong Kong, Hong Kong, China;Queen Mary Hospital, Hong Kong SAR, China

Christopher Chang Division of Pediatric Immunology and Allergy, JoeDiMaggio Children’s Hospital, Hollywood, FL, USA;Division of Rheumatology, Allergy and Clinical Immunology, University ofCalifornia Davis, Davis, CA, USA

Rosemarie H. DeKruyff Division of Pulmonary and Critical Care Medicine,Department of Medicine, Sean N. Parker Center for Allergy and Asthma Researchat Stanford University, Stanford, CA, USA

Valérie Devauchelle-Pensec INSERM U1227, «Lymphocyte B etautoimmunité», Labex Igo “Immunotherapy Graft, Oncology”, Réseauépigénétique du cancéropole Grand Ouest, Université de Brest, Brest, France;Department of Rheumatology, CHU Cavale Blanche, Brest University MedicalSchool, Brest, France

Johann E. Gudjonsson Department of Dermatology, University of Michigan,Ann Arbor, MI, USA

xii Editors and Contributors

Gan Huang Department of Metabolism and Endocrinology, The Second XiangyaHospital, Central South University, Changsha, Hunan, China;Key Laboratory of Diabetes Immunology (Central South University), Ministry ofEducation, National Clinical Research Center for Metabolic Diseases, Changsha,Hunan, China

Matlock A. Jeffries University of Oklahoma Health Sciences Center, OklahomaMedical Research Foundation, Oklahoma City, OK, USA

Christelle Le Dantec INSERM U1227, «Lymphocyte B et autoimmunité», LabexIgo “Immunotherapy Graft, Oncology”, Réseau épigénétique du cancéropole GrandOuest, Université de Brest, Brest, France

Yikang Li Department of Gastroenterology and Hepatology, Renji Hospital,School of Medicine, Shanghai Jiao Tong University, Shanghai Institute ofDigestive Disease, Shanghai, China

Andrew Long Division of Pulmonary and Critical Care Medicine, Department ofMedicine, Sean N. Parker Center for Allergy and Asthma Research at StanfordUniversity, Stanford, CA, USA;Department of Pharmacy, Lucile Packard Children’s Hospital, Stanford, CA, USA

Qianjin Lu Department of Dermatology, Hunan Key Laboratory of MedicalEpigenomics, Second Xiangya Hospital, Central South University, Changsha,Hunan, China

Yangyang Luo Department of Dermatology, Hunan Children’s Hospital,Changsha, China

Xiong Ma Division of Gastroenterology and Hepatology, Key Laboratory ofGastroenterology and Hepatology, Ministry of Health, State Key Laboratory forOncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Shanghai, China

Zhanglei Mu Department of Dermatology, Peking University People’s Hospital,Beijing, China

Kari C. Nadeau Division of Pulmonary and Critical Care Medicine, Departmentof Medicine, Sean N. Parker Center for Allergy and Asthma Research at StanfordUniversity, Stanford, CA, USA

Yves Renaudineau INSERM U1227, «Lymphocyte B et autoimmunité», LabexIgo “Immunotherapy Graft, Oncology”, Réseau épigénétique du cancéropole GrandOuest, Université de Brest, Brest, France;Laboratory of Immunology and Immunotherapy, Brest University Medical School,CHU Morvan, Brest, France

Vanitha Sampath Division of Pulmonary and Critical Care Medicine, Departmentof Medicine, Sean N. Parker Center for Allergy and Asthma Research at StanfordUniversity, Stanford, CA, USA

Editors and Contributors xiii

Carlo Selmi Humanitas Clinical and Research Center—IRCCS, Rozzano, Milan,Italy;BIOMETRA department, University of Milan, Milan, Italy

Shuai Shao Department of Dermatology, Xijing Hospital, Fourth Military MedicalUniversity, Xi’an, Shannxi, China;Department of Dermatology, University of Michigan, Ann Arbor, MI, USA

Ruqi Tang Department of Gastroenterology and Hepatology, Renji Hospital,School of Medicine, Shanghai Jiao Tong University, Shanghai Institute ofDigestive Disease, Shanghai, China

Haijing Wu Department of Dermatology, Hunan Key Laboratory of MedicalEpigenomics, Second Xiangya Hospital, Central South University, Changsha,Hunan, China

Rong Xiao Department of Dermatology, The Second Xiangya Hospital, CentralSouth University, Changsha, China

Zhiguo Xie Department of Metabolism and Endocrinology, The Second XiangyaHospital, Central South University, Changsha, Hunan, China;Key Laboratory of Diabetes Immunology (Central South University), Ministry ofEducation, National Clinical Research Center for Metabolic Diseases, Changsha,Hunan, China

Jianzhong Zhang Department of Dermatology, Peking University People’sHospital, Beijing, China

Lian Zhang Department of Dermatology, Hunan Key Laboratory of MedicalEpigenomics, Second Xiangya Hospital, Central South University, Changsha,Hunan, China

Zhiguang Zhou Department of Metabolism and Endocrinology, The SecondXiangya Hospital, Central South University, Changsha, Hunan, China;Key Laboratory of Diabetes Immunology (Central South University), Ministry ofEducation, National Clinical Research Center for Metabolic Diseases, Changsha,Hunan, China

xiv Editors and Contributors

Part IIntroduction

Chapter 1Epigenetics in Health and Disease

Lian Zhang, Qianjin Lu, and Christopher Chang

Abstract Epigeneticmechanisms,which includeDNAmethylation, histonemodifi-cation, and microRNA (miRNA), can produce heritable phenotypic changes withouta change in DNA sequence. Disruption of gene expression patterns which are gov-erned by epigenetics can result in autoimmune diseases, cancers, and various othermaladies. Mechanisms of epigenetics include DNA methylation (and demethyla-tion), histone modifications, and non-coding RNAs such as microRNAs. Comparedto numerous studies that have focused on the field of genetics, research on epige-netics is fairly recent. In contrast to genetic changes, which are difficult to reverse,epigenetic aberrations can be pharmaceutically reversible. The emerging tools ofepigenetics can be used as preventive, diagnostic, and therapeutic markers. With thedevelopment of drugs that target the specific epigenetic mechanisms involved in theregulation of gene expression, development and utilization of epigenetic tools are anappropriate and effective approach that can be clinically applied to the treatment ofvarious diseases.

Keywords DNA methylation · Histone modification · miRNA · Immunedysfunction · Checkpoints · Signaling pathways · Cytokines

L. Zhang · Q. LuDepartment of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second XiangyaHospital, Central South University, Changsha, Hunan, China

C. Chang (B)Division of Pediatric Immunology and Allergy, Joe DiMaggio Children’s Hospital, Hollywood,FL 33021, USAe-mail: chrchang@ucdavis.edu

Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis,Davis, CA 95616, USA

© Springer Nature Singapore Pte Ltd. 2020C. Chang and Q. Lu (eds.), Epigenetics in Allergy and Autoimmunity,Advances in Experimental Medicine and Biology 1253,https://doi.org/10.1007/978-981-15-3449-2_1

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4 L. Zhang et al.

1.1 Introduction

The realization that DNA sequence is not the sole determinant of clinical phenotypewas a result of the observation that identical twins,who carry the sameDNA, are oftendisease discordant, whereby one of the twins is sick and the other is healthy (Fragaet al. 2005; Javierre et al. 2010; Costello et al. 2000). The term “epigenetic” was firstproposed byWaddington (1939), who introduced the term “epigenetic landscape” todescribe the molecular and biologic mechanisms that transform a genetic trait into avisualized phenotype. This encompasses the idea of the genotype and the phenotype(Esteller 2008; Rideout et al. 2001). Modulation of gene expression is a way that theDNA sequence can be regulated leading to stimulation or suppression of pathwaysor molecules that may lead to health or disease.

Currently, DNA methylation is a well-characterized and intensely studied epi-genetic modification tracing back to the research done by Mahler and Griffith in1969, who showed that DNA methylation may play an important role in the func-tion of long-term memory (Bird 2002). Besides DNA methylation, other epigeneticmodifications include histone modifications, miRNA and nucleosome accessibility(Fig. 1.1). The continuous interest in epigenetics has resulted in discoveries of a rolefor epigenetics in diseases ranging from autoimmune diseases to cancer, congenitaldisease, mental retardation, endocrine diseases, pediatric diseases, neuropsychiatricdisorders, and many others (Fraga et al. 2005; Javierre et al. 2010).

Fig. 1.1 Primarymechanisms of epigeneticmodifications include DNAmethylation, histonemodifications, miRNA, andnucleosome accessibility

1 Epigenetics in Health and Disease 5

1.2 The Science Behind Epigenetics

The central dogma in genetics is the doctrine that information in our cells flowsonly in one direction—from DNA to RNA to proteins (Portela and Esteller 2010).It was an absolute dogma that has now been essentially debunked, due to the role ofthe environment in modulating the expression of genes. A new term, “epigenetic”,literally meaning outside of or above the gene, has become one of the hottest andnewest emerging fields in the scientific world. Epigenetics does not involve thebiochemical alteration in DNA sequences, rather, it turns on or off different genesthat can make us susceptible to developing disease.

Epigenetic research aims to unearth how environment, social condition, psychoso-cial factors, and nutrition affect an individual’s expression of genetic information(Fig. 1.2). In multicellular organisms, variable phenotypes may result from the samegenotype because of the potential ability of epigenetic markers appearing duringdevelopment to be passed on to offspring (Kaminsky et al. 2009). Researchers havealready found that the phenomenon of division and differentiation of single cellduring embryogenesis is tightly associated with epigenetics (Meissner et al. 2008).The result is that monozygotic twins have the same genetic information, but mayhave a different epigenetic profile, determined by the environment in which they liveand grow, leading to differences in health and disease phenotype (Kaminsky et al.2009). Theoretically, a cloned animal, with genetic material from the same donor,can potentially develop a different disease from the donor (Costello et al. 2000).Epigenetics can be part of the answer to variable phenotypes and plays a crucial rolein cell division and differentiation.

Fig. 1.2 The interactionamong epigenetics, genetics,and the environment

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1.3 Epigenetics and Human Disease

The three main mechanisms of epigenetics are DNA methylation, histone modifi-cation, and miRNA. These mechanisms are responsible for the initiation and main-tenance of epigenetic silencing and regulation of the gene expression profile andare cornerstones of a series of cellular processes, including cell differentiation, geneexpression, X chromosome inactivation, embryogenesis, and genomic imprinting(Holliday and Pugh 1975; Riggs 1975). Unveiling the relationship among thesecomponents has rapidly and surprisingly resulted an improved understanding of reg-ulation of gene expression. Furthermore, disruption of an epigenetic profile can havea significant impact on cellular function, which can lead to dysregulation of geneexpression and can potentially lead to the occurrence and development of “epigeneticdisease”.

An aberrancy in DNA methylation is a common manifestation of epigenetic dis-ease. Methylation occurs at the 5′-position of a cytosine residue, which is regardedas a fundamental gene silencing mark (Holliday and Pugh 1975). This cytosineresidue can be methylated and maintained by numerous DNA methyltransferases(DNMTs), which play an important role in the silencing of transcription factors, aswell as defense against expression of endogenous retrovirus genes and repressionof transposable elements (Roulois et al. 2015). The addition of a methyl group tothe untouched C-5 position of a cytosine by DNMTs during DNA replication con-tributes to the occurrence of de novo DNAmethylation (Jones and Baylin 2002). Themethylation occurring in 5′-CG-3′(CpG) can easily be deaminated spontaneously tothe thymine, while the unmethylated CpGs can be converted to uracil. The expectednumber of CG pairs in the human genome is about 20% (Jones 2012). The observednumber is often lower than the expected number, due to a high mutation rate formethylated CpG sites.

Some promoter regions enriched with CG, named CpG islands, are at least 200 bpand are greater than 55% conserved throughout evolution. Maintaining the primaryepigenetic status is fundamental to maintaining normal development. Disruptionof this balance can lead to an aberrant epigenetic landscape on the basis of timeand place. The DNA located at some promoter regions, when methylated, maycause heritable transcriptional silencing. The hypermethylation occurring at someimportant genes, such as p16INK4A, CDH1, DAPK, p14ARF, can contribute to thetumorigenesis (Esteller 2007).

Histone modification is another key mechanism of epigenetics (Fig. 1.3). Histonecomplexes are composed of two unstable dimers H2A, H2B and a tetramer of H3 andH4, wrapped by 147 bp of DNA to form the nucleosome (Schotta et al. 2004). Thehistone complex facilitates the condensation of genomic DNA and has an impact onpost-transcriptional modification. Several modifications, such as acetylation, methy-lation, ubiquitination, phosphorylation, and sumoylation, occur on the conservedlysine at the histone tails (Nakayama et al. 2001; Yuen and Knoepfler 2013).

Histone acetylation and deacetylation are essential for gene regulation. Acetyla-tion generally leads to active transcription, whereas hypoacetylation is an indicator of

1 Epigenetics in Health and Disease 7

Fig. 1.3 Histonemodifications includeacetylation, methylation,ubiquitination,phosphorylation, andsumoylation

inactive transcriptionally. Histone methylation can indicate both active and inactivetranscription, and the state of mono-, di-, and trimethylation has different effects.Methylation is facilitated by the enzymes known as histone methyltransferases(HMT).

Histone modification to H3 is the most well studied and characterized. The di-and trimeric forms of H3K4 and H3K36 are frequent targets of histone modificationand lead to activation of transcription. In contrast, H3K92/3 and H3K27me2/3modification lead to gene silencing. It should be noted that the histone componentH3K9 is found primarily in a gene-poor region, such as telomeres and centromeres,and is a permanent marker for the formation of heterochromatin. This histonecomponent is also associated with X chromosome inactivation and gene repressionat promoter regions (Nakayama et al. 2001). Conversely, the H3K27 is generallyfound in gene-rich regions and acts as a temporary marker correlating with thedevelopment of regulators (Santenard et al. 2010). Studies show that histone H3mutations are associated with giant bone cell tumor and chondroblastoma and havealso been found to be a mutation of high frequency in high-grade gliomas in children(Schwartzentruber et al. 2012). Any mutation of histone-associated enzymes maycontribute to the development of diseases, such as cancers, autoimmune diseases,endocrine diseases, and psychologic disorders.

Mature miRNA is another key player in epigenetics. miRNA is a class of non-coding small RNA, about 22 nucleotides in length. MicroRNA are complementaryto single or a series of messenger RNA (mRNA). It cannot be translated into protein,rather their main function is to downregulate gene expression in different ways,including mRNA cleavage, translational inactivation, and deadenylation to producea mitotically heritable result (Tufarelli et al. 2003). Emerging evidence indicatesthat miRNAs play significant roles in cell division, differentiation, and development.Abnormalities in miRNA are associated with a wide variety of human diseases,

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including cancer, autoimmune diseases, and cardiac diseases (Calin et al. 2002).Consequently, miRNAs are becoming extremely useful as clinical biomarkers, anddiagnostic tools have been developed especially in the field of cancer. In addition,miRNA play a crucial role in many other biological systems. An example would bein cardiology. Through regulation of gene expression, miRNAs play a significant rolein regulating cardiac function or dysfunction, including cardiac rhythm, ventricularwall integrity, contractility, and myocyte growth.

1.4 The Clinical Application of Epigenetics

Oneof the personal human challenges in health and disease has to dowith uncertainty.In the vast majority of cases, there is no single test that will definitely provide ananswer for patients. Patients often need multiple studies, which take a significantamount of time, and this adds to the anxiety of seeing a physician. The promise ofepigenetic is that it can provide new insights into clinical development of diagnosticand therapeutic methods and bridge the gap between effects of the environment andhost genetics. Epigenetics has the potential to be used as biomarkers for the detectionand diagnosis of disease, disease monitoring, and response to treatment. In the pastfew decades, pharmacoepigenetics has attracted much interest and epigenetic drug(epidrug) development has achieved significant advancement.

1.4.1 Epigenetic Biomarkers

The discovery and utilization of biomarkers have the potential to impact patientmanagement and clinical outcomes (Garcia-Gimenez et al. 2017).Biomarkersmaybedirectly related to pathogenesis or may be surrogate markers or important for diseaseprognostication or monitoring. Some biomarkers may also be potential therapeutictargets or may indicate where the search for such targets should commence (Costa-Pinheiro et al. 2015; Dirks et al. 2016). The identification of potential markers isonly the first step, as these markers must be validated and confirmed as a reliable andstatistically acceptable reflection of the disease. Epigenetic markers have alreadybeen incorporated into clinical application and are being used in the prevention,diagnosis, and treatment of cancers, autoimmune diseases, as well as neurologicaland cardiac disorders.

There are several advantages of epigenetic biomarkers. First, the biomarkers indi-cate a new direction in which molecular markers correlate with genetic and theenvironmental factors which contribute to the development of diseases (Lorincz2011). What epigenetics does is to provide a functional biomarker which does notdepend on DNA sequence alone. The epigenetic biomarker, especially those relatedto DNA methylation, falls outside of the DNA and RNA sequence based testing andmay provide an alternate stability profile (Garcia-Gimenez et al. 2017). Epigenetic

1 Epigenetics in Health and Disease 9

biomarkers can be checked in blood, tissue, body fluid as well as secretions which arecommonly sampled during procedures and surgeries. Furthermore, any disruption ofepigenetics can be checked in the context of the genome and even prior to or at thevery early stage of the disease. This property is unique compared to the RNA andprotein-based tests because RNA and protein abnormalities appear at relatively latestages and often in low quantities or concentration.

1.4.2 Epigenetic Therapy

Epigenetic therapy is a new treatment option utilizing epigenetic drugs (epidrug) orless obviously, non-pharmacological techniques of clinical management (Fig. 1.4).Recent research in epigenetics now offers an attractive way to target the epigeneticmechanism caused by cancers, autoimmune diseases, cardiac disorders, and mentalillness.

Large numbers of molecular inhibitors have been developed over the past sev-eral decades. The United States Federal Drug Administration (FDA) approved thefirst epidrugs azacytidine (5-AZA) and decitabine (5-AZA-CdR) in 2004 for thetreatment of leukemia (Egger et al. 2004). These drugs are in fact DNAmethyltrans-ferase inhibitors, thereby categorized as epigenetic modifiers, which can reprogramthe epigenetic profile and potentially reverse the disease. They are now indicatedin the treatment of hematologic malignancies, including acute myeloid leukemia(AML), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia(CMML). Reprogramming and reshaping the epigenetic profile by reducing DNA

Fig. 1.4 Epidrugs for the treatment of human diseases. Several epidrugs have been approved forclinical application, and many epidrugs are undergoing clinical trials

10 L. Zhang et al.

Table 1.1 A variety of epidrugs are already approved for clinical use or are undergoing clinicaltrials

Drug Disease phrase clincal applica onHDACiAzaci dine CMML,AML and MDS clincial prac ce For the treatment of haematological malignancies Decitabine CMML,AML and MDS clincial prac ce For the treatment of haematological malignancies Guadecitabine AML Phase III clinical trial Recruited AML pa ents HDACiVorinostat CTCL clincial prac ce For the treatment of CTCLBelinostat PTCL clincial prac ce For the treatment of PTCLPanobinostat HIV-1 Phase I/II clinical trial Recruited HIV pa ents Pracinostat AML Phase III clinical trial Recruited AML pa ents HDMiGSK2879552 Relapsed/refractory SCLC Phase II clinical trial Recruited SCLC pa ents INCB059872 Advanced malignancies Phase I/II clinical trial Recruited AML/MDS pa ents Tranylcypromine Bipolar depression Phase IV clinical trial Recruited bipolar depression pa ents HMTiTazemetostat Refractory B cell (NHL) Phase I/II clinical trial Recruited NHL pa ents MAK683 DLBCL Phase I/II clinical trial Recruited DLBCL pa ents

methylation levels, especially on tumor suppressor genes, may lead to normalizationof the gene expression profile (Table 1.1).

Histone acetylase inhibitors are another compelling class of epidrugs (Nagarajaet al. 2017). Panobinostat has been approved for the treatment of multiple myeloma(MM), Belinostat has been used in the treatment of refractory or relapsed peripheralT cell lymphoma (PTCL), and several clinical trials using sodium phenylbutyratefor Huntington disease and Vorinostat for HIV-1 are undergoing (Vojinovic et al.2011). Other oncology research is focusing on the combination treatment of HDACand DNMT inhibitors for AML, glioma, breast cancer, and CMML, thereby demon-strating a synergistic effect (Brocks et al. 2017) between two forms of epigeneticmechanisms.

Drug resistance remains a problem (Grasso et al. 2015). EZH2, one of the compo-nents of polycom-repressive complex 2 (PRC2), is a histone K27 methyltransferase.Recent studies on the EZH2 inhibitor have shown an arrest of cell growth by itsability to remove residual PRC2 (Mohammad et al. 2017). In a recent trial, an EZH2inhibitor, tazemetostat, has been tested to treat refractory B cell lymphoma (NHL)(Morera et al. 2016). Another team is using MAK683, an inhibitor of embryonicectoderm development protein (EED), to treat nasopharyngeal carcinoma and diffuselarge B cell lymphoma (DLBCL) (Chiappella et al. 2017).

Epidrugs have showed promising effects in both clinical practice and preclinicaland clinical trials. Scientists are not only focusing on the enzymes that generate orcreate epigenetic markers (readers), but also on the enzymes that wipe out epigeneticmarkers (erasers) and proteins that edit epigenetic markers (writers).

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1.5 Epigenetic in Diseases

1.5.1 The Role of Epigenetics in Cancer

Epigenetic aberration is a common feature of cancer, characterized by hyperme-thylation at specific promoter regions and global DNA hypomethylation, and/oreither loss or gain of acetylation or methylation of histone proteins (Liang andWeisenberger 2017). Disruption of chromatin is crucial for nucleosome positioning,DNA wrapping, accessibility of chromatin to transcription factors, and regulation ofgene expression. Silencing of tumor suppressor genes and activation of oncogenesare the hallmarks of epigenetic aberrancy (Fig. 1.5). The dysregulation of theepigenetic profile plays a key role in carcinogenesis. Likewise, the dynamic andreversible character of epigenetic modulation is an attractive feature for novelclinical treatment modalities.

1.5.1.1 AML

AML is a malignant tumor that arises from abnormal hematopoietic stem cells, char-acterized by massive proliferation of neoplastic precursor tumor cells, which causeshematopoietic aberrancies and alters bonemarrow homeostasis. Current clinical pro-tocols have limited options, involving intensive chemotherapy (Lavallee et al. 2016),and/or using poorly sourced stem cell transplantation (Powles et al. 1980). Despitepromising results over the last few decades, AML is still a devastating disease inover half of young patients and almost 80% of elderly patients due to relapse anddrug resistance, leading to increased morbidity and mortality (Adelman et al. 2019;Burnett et al. 2011). Aberration of the epigenetic landscape contributes to the devel-opment and the regulation of AML. Recurrent somatic mutations occur in specificgenes that play a crucial role in epigeneticmodulation, but epigenetic dysregulation is

Fig. 1.5 Epigeneticmechanism in cancerswhich are induced by bothDNAmethylation and histonemodifications can be reversed by inhibitors of epigenetic modifiers

12 L. Zhang et al.

a more likely mechanism compared to the recurrent mutations alone. Consequently,there is an urgent need to unearth the epigenetic mechanisms and pathogenesis ofAML in order to achieve better patient management.

DNA MethylationAberrant DNA methylation is a hallmark of cancer, with global hypomethylation atrepetitive elements, and hypermethylation occurring in the promoter regions that areenriched with CpG islands. Emerging evidence shows that for leukemogenesis, thedisruption of DNAmethylation occurring outside of CpG island is equally importantas those within CpG island regions, and that hypomethylation and hypermethylationcontribute equally to oncogenesis. Recent studies show thatmyeloidmalignancies areaccompanied by recurrentmutations occurring at epigeneticmodifiers including Tet2and DNMT3A, which are associated with hypomethylation and hypermethylation.Unearthing the interaction of these DNAmethylation modifiers can help to elucidatethe mechanism of AML.

DNMT3A is a DNAmethylation enzyme that can produce de novo methylation atCpG loci, and it is a common target of somatic mutations. These mutations occur inalmost 40% of cytogenetic AML patients and about 20% of T-AML patients (Shlushet al. 2014). DNMT3A is viewed as a marker of early stage leukemia and may bebeneficial in monitoring early events in AML. Increasing evidence has shown thatDNMT3A mutations which occur in AML may appear in the T lymphocytes fromthe same individual.

Recent research has also demonstrated that elderly people can carry theDNMT3Amutation without evidence of hematologic malignancy, showing that these muta-tions may be involved in clonal hematopoiesis and can contribute to leukemogenesis(Bond et al. 2019). The mutation occurring in DNMT3A leads to an arginine substi-tution, which results in a reduction in enzyme activity (Russler-Germain et al. 2014).DNMT3A mutated mice showed dynamic DNA methylation patterns occurring inboth regions of hypomethylation and hypermethylation. Normal DNMT3A is crit-ical for HSC self-renewal and cell differentiation in adult wild-type recipient mice(Liu et al. 2005). DNMT1 is a key player in the fate of leukemia cells, and a defi-ciency of DNMT1 in a mouse model was associated with reduced DNAmethylationwith reduction of the capacity of tumor suppressor genes to reactivate (Mizuno et al.2001).

The ten-eleven translocation (TET) family is another important target ofDNA methylation through the transformation of 5-methyl-cytosine (5-mc) to 5-hydroxymethylcytosine (5-hmc). About 30% of AML patients have mutations inTET2, which leads to reduced 5-hmc levels (Cimmino et al. 2017). The associa-tion between TET mutations and poor prognosis of AML patients has been reported.Increased capacity of self-renewal, over-proliferation of hematopoietic stem and pro-genitor cells (HSPC), and increased cell differentiation have been observed in TET2deleted mice. In about 30% of AML patients, mutations frequently occur in isoci-trate dehydrogenase 1 and 2 (IDH1 and IDH2). Mutated TET and mutated IDH aremutually exclusive in adult AML. IDHcan convert isocitrate intoα-ketoglutarate nat-urally, but 2-hydroxyglutarate (2-HG) results frommutated IDH. Thismetabolite can

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compete with α-ketoglutarate and function as an inhibitor of TET2. Furthermore, theglobal hypermethylation signature in AML is associated with mutated IDH1/IDH2,and the overlapping hypermethylation signature has been observed in patients withmutated TET2. Murine models show that the level of 2-HG is increased in mutatedIDH and the population of HSPC is expanded. Mouse findings were also consistentwith those in AML patients (Cimmino et al. 2017).

Histone ModificationHistone acetyltransferases (HAT) and histone deacetylases (HDACs) are the primarymediators of histone acetylation and deacetylation, respectively. HAT is involved insporadic translocation in AML patients (Izutsu et al. 2001). The myeloid oncopro-teins, including PML-RARA and EVI-1, can interplay with either major complexesor scaffold proteins which aberrantly recruit HDACs. This results in abnormal chro-matin condensation and remodeling, with the sites near transcription factors beingmore affected. HMTs are involved in translocation in AML, and HMT mutationsoccur in components of PRC2 andmixed-lineage leukemia (MLL) proteins (Basheeret al. 2019). The most common MLL protein, KMT2A, can modify H3K4 and tran-scriptionally activate targeted genes. MLL-induced translocations occur in about10% of AML patients.

Abnormal patterns of H3K79 methylation have been observed in MLL-transformed AML patients, and several related genes are also overexpressed. EZH2can stimulate the di- and trimethylation of H3K27 and is generally considered to bea repressive modifier in numerous types of malignancies. Intriguingly, EZH2 muta-tions result in functional silencing in ALL, but themechanism remains unclear. Othercomponents, including SUZ12 and EED, play an important role in the leukemogen-esis. Mutations of these components can lead to loss of function in ALL (Sinha et al.2015).

miRNAAberrant activity of certain miRNAs can disrupt hematopoiesis and trigger leuke-mogenesis (Liu et al. 2019). miRNA can perform as either tumor suppressor oroncogenic agents, and while many new miRNAs are being found to have epigeneticactivity each year, there are many that probably have not even been identified.

The most studied miRNA in AML is Let-7, which is known for its tumor-suppressive property in various types of cancers. It functions by targeting a numberof different oncogenes, including KRAS, HMGA2, MYC, and IMP1, and plays arole in adult AML. Let-7b is also downregulated in pediatric AML patients, and itis associated with dysregulation of the oncogene c-Myc, indicating that both solidtumors and hematologic neoplasia may have abnormal expression of Let-7 (Pelosiet al. 2013). Another well-known miRNA is miR-29, which is downregulated inMLL-mediated AML. The main function of miR-29 is induction of apoptosis andregulation of the cell cycle. Studies in mice support that miR-29 can induce apoptosisand inhibit tumor cell growth (Garzon et al. 2009).

Oncogenic miRNAs such as miR-126 play a significant role in cancer. Overex-pression ofmiR-126 in stable leukemia cell lines demonstrates inhibition of apoptosis

14 L. Zhang et al.

and improved cell survival. AML patients also may show high levels of miR-24, andoverexpression of miR-24 blocks the synthesis of mitogen-activated protein kinasephosphatase 7, promoting cell growth in AML (Organista-Nava et al. 2015).

1.5.1.2 Lung Cancer

Lung cancer is the leading cause of tumor-related death worldwide and is responsiblefor nearly 30% of cancer-related deaths, which is significantly more than the othertop five cancers, including colorectal carcinoma, breast and prostate cancer. Despitemedical advances, lung cancer continues to have a high mortality and low survivalrate. Environmental tobacco smoke continues to be an important risk factor. Lungcancer can be clustered into two groups, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The latter group can be further categorized intotwo types, squamous cell lung cancer and adenocarcinoma. The abnormal initiationand progression of lung cancer may be caused by the interplay of genetic disruptionand dynamic epigenetic aberrancies. Epigenetics plays a key role and is an attractivetarget for the study of lung cancer and the development of new treatments.

DNA MethylationStudies of the abnormal epigenetic profile seen in lung cancers can improve ourunderstanding of lung tumorigenesis. Aberrations in DNAmethylation is a key factorthat contributes to the initiation and development of lung cancer by silencing tumorsuppressor genes. DNA hypermethylation at promoter genes is considered an earlyevent, and about 3% of functional genes carrying CpG-rich regions are deactivatedin advanced stages of lung cancer (Teixeira et al. 2019). Three DNMTs are widelystudied, all of which are overexpressed in lung cancer. The expression of DNMT1is increased at the early stage of lung cancer, and it can silence the expression ofP16INK4A and RASSF1A. DNMT3B is also a key participant in the pathogenesis oflung cancer and is associated with poor prognosis. The interaction of these DNMTsestablishes abnormal DNA methylation patterns and represses the expression oftumor suppressor genes. Numerous tumor suppressor genes are affected and silenced,including MGMT, CDH13, DAPK, and APC genes. The inactivation of RASSF1Aoccurs in about 40% of squamous cell carcinomas and almost 80% of small cell lungcancers (Giri and Aittokallio 2019).

Histone ModificationGlobal H3 methylation and H2A acetylation have been observed in both SCLCand NSCLC. Gene activation caused by the H3K9 methyltransferase SETDB1 hasbeen observed in lung carcinogenesis and increases invasiveness of cancer cells andcell proliferation by regulation of the WNT pathway. ERK1/2 activation, inducedby upregulation of the H3K36 modifier KDM2A, promotes invasiveness and cellgrowth and is associated with a poor prognosis (Gardner et al. 2017). There are othermetastasis-associated genes activated through upregulation of H2F3A, increasing

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tumor invasiveness resulting in poor outcomes in early stages of lung cancer. Like-wise, upregulation of H4K8 acetylation and hypoacetylation of H3K12/H4K16 havebeen reported to occur in squamous cell carcinoma (Roper and Sheng 2019).

miRNADownregulation of dicer has been observed in NSCLC and correlates with poorprognosis. A mouse lung cancer model showed that dicer deletion led to tumordevelopment and lower survivor rates (Szczyrek et al. 2019). miR199, miRNA101,and miRNA 126 are dysregulated in rat models in the early stage of lung cancer andare downregulated in human NSCLC patients as well. miRNA-let plays a crucial rolein cell apoptosis and the cell cycle; downregulation of let-7 promotes cell division inlung cell lines and upregulation inhibits cell growth. Xenograft mouse model studiesshow similar results.

A study of smokers who suffered fromNSCLC found that polymorphisms in let-7correlate with increased death risk (Del Vescovo and Denti 2015). miR-17-92 regu-lates cell apoptosis. Deactivation of let-7 and overexpression of MYC are commonfindings in lung cancer, leading to the upregulation of miR-17-92, overexpression ofE2F protein, and increased lung carcinogenesis. Furthermore, miR-17-92 increasesgenomic instability and RB repression in SCLC cell lines. RB repression results inDNA damage by inducing the expression of y-H2AX (Zhang et al. 2018).

1.5.1.3 Pediatric High-Grade Glioma

In the past few decades, medical advances have greatly improved the survival ratesof a number of pediatric cancers. This is not true for pediatric high-grade glioma(pHGG). Neurogenic tumors remain the leading cause of pediatric cancer, and pHGGis the leading cause of neurogenic tumors. It primarily affects the pons, brain stem,and cerebellum, with a survival rate lower than 1% (Donaldson et al. 2006). About80% of pHGG is associated with histone H3 mutations, where K27 lysine is substi-tuted by methionine (H3K27M) (Schwartzentruber et al. 2012). Treatment of pHGGis limited to surgery and radiation, with effective chemotherapy currently unavail-able. Research targeting epigenetics provides a potential novel alternative to currenttreatment modalities.

DNA MethylationDNA methylation patterns of pHGG show hypermethylation at CpG-rich promoterregions, leading to deactivation of tumor suppressor genes. H3K27Mmutations com-monly occur in pHGG affecting the midline structures and are associated with fewO6-methylguanine-DNA methyltransferase (MGMT) methylation changes, dismalresults, and poor prognosis (Wu et al. 2012; Taylor et al. 2014). Similarly, H3G34R/Vmutations are associated with a poor prognosis, whereas IDH1 mutations have nosignificant impact on survival rates compared to the wild type. H3G34R/V muta-tions are commonly associated with hemispheric pHGG with MGMT methylation

16 L. Zhang et al.

enrichment (Fang et al. 2018). The methylation profile of three proliferative onco-genes, pedGBM-RTK1, pedGBM-RTK2, and pedGBM-MYCN, are associated withpoor prognosis. DNAmethylation profiles present important information that can beused to determine treatment and prognosis.

Histone ModificationAn H3 mutation is identified as an oncohistone. Nearly 80% pHGGs harbor theH3.3K27M mutation, which has already been introduced (Schwartzentruber et al.2012). H3K27I is another mutation that occurs in H3.3, where a lysine is substi-tuted by an isoleucine. Furthermore, H3G34R/V, another variant of pHGG, involvessubstitution of glycine 34 to either arginine or valine. Mutations of H3.1 and H3.2,including HIST1H3B and HIST1H3C, are common events leading to histone vari-ations named H3.1K27M and H3.2K27M, respectively. Mutations of H3.3 K27MandG34R/V occur exclusively in pHGG and show unique DNAmethylation patternsand gene expression profiles.

Interestingly, these two types of mutations in H3.3 often occur simultaneouslywith mutations in other genes. For example, nearly 30% of the K27M mutations areassociated with an ATRX mutation and approximately 60% of mutations occur inconjunction with a TP53 mutation. Likewise, G34R/V mutations have ATRX andTP53 mutation as well, but the PDGFRA mutation has been found in the same indi-viduals (Yuen and Knoepfler 2013). Together, this evidence suggests that mutationsin H3 are an important risk factor and contribute to the pathogenesis of pHGG. Sci-entists have found that HDAC inhibitors have a promising effect on the treatment ofpHGG (Grasso et al. 2015; Pang et al. 2009). According to this study, a combinationof HDAC inhibitors, BRD4 and CDK7 blockers are a better strategy to overcomedrug resistance (Nagaraja et al. 2017). EZh2 inhibitor, another inhibitor of histonemodification, can remove PRC2 and inhibit cell growth and may be a promisingtherapeutic method for the treatment of pHGG (Mohammad et al. 2017).

miRNAStudies ofmiRNA in pHGGare lacking compared to adult gliomas. The expression ofmiR-34 andmiR-21 are upregulated, whilemiR-129 andmiR-124 are downregulatedin pHGG. Several miRNAs are involved in the regulation of gene expression throughthe MAPK pathway, involving regulation of BRAF-KIAA1549 (Pang et al. 2009).A xenograft mouse model of miR-487 showed inhibition of colony formation anddownregulation of nestin and PROM1 genes. Other miRNA, including miR-204,miR-1296, miR-1224, miR-10a, and miR-34c, are downregulated, and miR-527,miR-769-3, and miR-200A are upregulated in pHGG (Riddick and Fine 2011).

1.5.2 The Role of Epigenetics in Immune Diseases

The etiology of autoimmune diseases remains unclear. Although genome-wide asso-ciation studies (GWAS) are now widely available, they have failed to reveal a cleargenetic pathophysiology of autoimmune diseases. Scientists now appreciate that the

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Fig. 1.6 Epigenetic modifications dysregulate gene expression on different types of immune cellsand trigger autoimmune diseases

epigenome plays a critical role to initializing and stimulating autoimmune diseases(Fig. 1.6). Disruption of DNA methylation and histone modification leads to abnor-mal epigenetic profiles. Epigenetic aberration in autoimmunedisease results in break-ing self-tolerance, thus triggering autoimmunity. The epigenetics of autoimmunediseases is discussed in Chaps. 7–13 of this book.

1.5.2.1 Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterizedby overactivation of the immune system and production of excessive autoantibodies.These antibodies may attack self-tissues or organs and are a potential cause of SLE.However, even with the medical advances of the past decades, the mechanism ofSLE remains unclear. Epigenetics may provide new insights to elucidating some ofthe factors leading to the breakdown of tolerance.

DNA MethylationDNA methylation is a key player in the pathogenesis of SLE. Altered DNA methy-lation in SLE is characterized by global hypomethylation on CD4+ T cells involv-ing the extracellular signal-regulated kinase (ERK) signaling pathway. In murinemodels, studies have shown dysregulation of this pathway leading to downregula-tion of DNMT1 and overexpression of methylation-associated autoimmune genes.