Patho-Epigenetics of Disease
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1 Patho-Epigenetics of Disease
2
3 Janos Minarovits Hans Helmut Niller Editors Patho-Epigenetics of Disease
4 Editors Janos Minarovits Microbiological Research Group National Center for Epidemiology Budapest, Hungary Hans Helmut Niller Institute for Medical Microbiology and Hygiene at the University of Regensburg Regensburg, Germany ISBN ISBN (ebook) DOI / Springer New York Heidelberg Dordrecht London Library of Congress Control Number: Springer Science+Business Media New York 2012 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, speci fi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on micro fi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied speci fi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a speci fi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (
5 Preface Epigenetic regulatory mechanisms ensure the heritable transmission of gene expression patterns from one cell generation to another, helping progeny cells to remember their proper cellular identity. Thus, epigenetic alterations, including DNA methylation, DNA-associated Polycomb Trithorax complexes, and histone modi fi cations, provide the means for establishment, maintenance, and programmed alterations of cell type-speci fi c gene expression patterns in multicellular organisms. There is a complex interplay between the various epigenetic processes resulting in the unique transcriptional activity and phenotypic diversity of cells carrying identical or nearly identical DNA sequences. These carefully orchestrated processes can go wrong, however, resulting in epigenetic reprogramming of cells which may manifest in pathological changes, as it was fi rst realized, as far as we know, during the studies of epigenetic alterations in malignant tumors. Patho-epigenetics is a new discipline dealing with the pathological consequences of dysregulated epigenetic processes (Minarovits 2009 ). In recent years, epigenetic ideas found their way into many areas of medical and veterinary research, and this new attitude helped to explore many unexpected but most important aspects of disease initiation and progression. This book focuses mainly on patho-epigenetic alterations observed in human diseases, although animal models and veterinary diseases are also touched where relevant. Deciphering how the host cell epigenome is changing in diseased cells and organs may help to develop new tools permitting early and stage-speci fi c detection of pathological alterations. It may lay the foundation of epigenetic therapies, too. The goal of this book is to bring together recent results of epigenetic research with special attention to disease development. The fi rst chapter by Walter Doerfler, senior of epigenetics research in virology, puts epigenetic research into historical context, reviewing the impact of foreign DNA insertion on the epigenotype of the host cell, and vice versa, with all of its vanguard implications for carcinogenesis and evolution. Next, Sole Gatto, Maurizio D Esposito, and Maria R. Matarazzo describe how distinct mutations of the de novo DNA methyltransferase DNMT3B cause ICF syndrome (Immunode fi ciency, Centromeric region instability, and Facial anomalies v
6 vi Preface syndrome), a very rare autosomal recessive disease. In addition to describing the consequences of DNMT3B loss-of-function mutations, they also present a novel view regarding the setting and maintenance of DNA methylation in mammals and discuss mouse models of maintenance and de novo DNA methyltransferase deficiencies. DNA stretches rich in methylated cytosine are preferentially bound by methyl- CpG binding proteins implicated in the establishment of repressive chromatin structures that are unfavorable for transcription. Gaston Caifa, Alan K. Percy, and Lucas Pozzo-Miller outline how mutations in the MECP2 gene coding for methyl-cpgbinding protein-2 cause Rett syndrome (RTT), a sporadic neurodevelopmental disorder characterized by cognitive impairment, communication dysfunction, and stereotypic hand movements. They also discuss how the classical view of MECP2 as a global transcriptional repressor changed in the light of new data demonstrating its role in gene activation and alternative splicing. The role of MECP2 and its murine counterpart in brain development is demonstrated in KO and knock-in mouse models, as well as the reversion of many RTT-like symptoms in mice reared in enriched environments. Glioblastoma multiforme (GBM), the most common malignant brain tumor of adults is the topic of John K. Wiencke who argues that the patho-epigenetic background of primary GBM differs from that of secondary GBM arising in patients with a prior history of a non-gbm brain tumor. He emphasizes the importance of isocitrate dehydrogenase mutations resulting in the production of 2-hydroxyglutarate, an oncometabolite implicated in the inhibition of TET (ten-eleven-translocation) family enzymes that mediate active DNA demethylation. These processes may result in DNA hypermethylation at hundreds of gene loci in secondary GBMs and a fraction of de novo GBMs. Epigenetic dysregulation in breast cancer, the most common non-skin malignancy affecting women in the Western world is discussed by Amanda E. Toland. She overviews not only the contribution of DNA methylation, Polycomb repressor complexes, and histone modi fi cations to breast carcinogenesis, but in addition to these classical epigenetic regulatory mechanisms she elegantly discusses the role of nuclear organization, chromatin looping, micrornas, and long noncoding RNAs (lncrnas) as well. These mechanisms are involved in transcriptional or posttranscriptional regulation and they are frequently discussed in an epigenetic context, although they may not contribute to heritable transmission of gene expression patterns. Hormonal dysbalance is an important factor in mammary carcinogenesis and affects the development and progression of prostate cancer as well, the topic of the review by Christian Arsov, Wolfgang Goering, and Wolfgang A. Schulz. They discuss both genetic and epigenetic alterations relevant to prostate carcinogenesis and describe putative epigenetic biomarkers for prostate cancer detection and prognosis. Drugs targeting epigenetic alterations in prostate cancer and their initial clinical trials are overviewed, too. Epigenetic changes characteristic for lung carcinoma, the leading cause of cancer mortality in the United States, is the topic of András Kádár and Tibor A. Rauch.
7 Preface vii They give a thorough description of hyper- and hypomethylation events, histone modi fi cation changes, and noncoding RNAs associated with lung carcinomas. The pharmacological aspects of DNA methylation-targeted therapy are also dealt with. Hans Helmut Niller, Ferenc Banati, Eva Ay, and Janos Minarovits discuss the epigenetic alterations frequently observed in virus-associated malignant tumors. They focus on the epigenetic marks of latent gammaherpesvirus genomes related to the host cell-dependent expression of Epstein Barr virus (EBV) and Kaposi s sarcoma-associated herpesvirus (KSHV) episomes and describe the interactions of the viral oncoproteins with the cellular epigenetic regulatory machinery. Pathoepigenetic processes related to human T-lymphotropic virus, hepatitis B virus, hepatitis C virus, human papillomavirus, Merkel cell polyomavirus, and the associated neoplasms are also discussed. Both genetic and epigenetic conditions appear to contribute to the pathological forms of aggression, the topic of Barbara Klausz, József Haller, Áron Tulogdi, and Dóra Zelena. They describe the relevant animal models and the pioneering studies on the epigenetic effects of steroid hormones, as well as serotonine, vasopressine, and neutrophins, in distinct areas of the brain that could be related to changes in behavior and review the data related to the reduction of aggressive behavior by a histone deacetylase (HDAC) inhibitor. Neuropsychiatric disorders also became the subjects of intense epigenetic studies. Dóra Zelena summarizes the epigenetic changes in schizophrenia (SCZ) and bipolar disorder (BD) which constitute a major public health burden. A series of complex epigenetic alterations were associated with the brain areas implicated in the development of SCZ. In BD, there were less numerous studies, although one of the HDAC inhibitors, valproate, is known to have a mood stabilizing effect. Epigenetic studies may contribute to the understanding of the etiology and molecular pathogenesis of autoimmune disorders as well. As discussed by Lorenzo de la Rica and Esteban Ballestar, epigenetic dysregulation may form the basis of as diverse systemic or organ-speci fi c diseases as systemic lupus erythematosus, rheumatoid arthritis, Crohn s disease, ulcerative colitis, autoimmune thyroid diseases, and many others. Certain genes are expressed only from one of the two parental alleles, and the disturbances of the epigenetic mechanisms regulating this process, called imprinting, cause growth restriction or overgrowth and behavior abnormalities. As summarized by Thomas Eggermann, imprinting disorders share molecular disturbances including aberrant methylation (epimutation), uniparental disomy, chromosomal aberrations, and point mutations in imprinted genes. Recently, epigenetic mechanisms were linked to the development of atherosclerosis as well. As overviewed by Einari Aavik, Mikko Turunen, and Seppo Ylä- Herttuala, dietary preferences may affect human health via epigenetic modi fi cations of chromatin structure. They speculate that a histone methylase may switch the phenotype of smooth muscle cells that may clonally expand in atherosclerotic plaques. Finally, Hans Helmut Niller, Ferenc Banati, Eva Ay, and Janos Minarovits describe the epigenetic changes associated with microbial infections. Certain viruses
8 viii Preface not associated with neoplasms, most remarkably human immunode fi ciency virus (HIV), may affect the epigenotype of the host cell. Bacterial toxins and effector molecules may change histone modi fi cation patterns and Helicobacter pylori, associated with gastric carcinoma, alters both DNA methylation and histone modi fi cation in its target cells. Unicellular protozoa have their own sophisticated epigenetic control systems, but their effects on the epigenome of the host organisms remains to be established. Budapest, Hungary Regensburg, Germany Janos Minarovits Hans Helmut Niller Reference Minarovits, J. (2009). Microbe-induced epigenetic alterations in host cells: the coming era of patho-epigenetics of microbial infections. A review. Acta Microbiol Immunol Hung 56, 1 19.
9 Contents 1 The Impact of Foreign DNA Integration on Tumor Biology and Evolution via Epigenetic Alterations... 1 Walter Doerfler 2 The Role of DNMT3B Mutations in the Pathogenesis of ICF Syndrome Sole Gatto, Maurizio D Esposito, and Maria R. Matarazzo 3 Dysfunction of the Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Gaston Calfa, Alan K. Percy, and Lucas Pozzo-Miller 4 Epigenetic Alterations in Glioblastoma Multiforme John K. Wiencke 5 Aberrant Epigenetic Regulation in Breast Cancer Amanda Ewart Toland 6 The Impact of Epigenetic Alterations on Diagnosis, Prediction, and Therapy of Prostate Cancer Christian Arsov, Wolfgang Goering, and Wolfgang A. Schulz 7 Epigenetic Reprogramming in Lung Carcinomas András Kádár and Tibor A. Rauch 8 Epigenetic Changes in Virus-Associated Neoplasms Hans Helmut Niller, Ferenc Banati, Eva Ay, and Janos Minarovits 9 Genetic and Epigenetic Determinants of Aggression Barbara Klausz, József Haller, Áron Tulogdi, and Dóra Zelena ix
10 x Contents 10 Co-Regulation and Epigenetic Dysregulation in Schizophrenia and Bipolar Disorder Dóra Zelena 11 Disruption of Epigenetic Mechanisms in Autoimmune Syndromes Lorenzo de la Rica and Esteban Ballestar 12 Imprinting Disorders Thomas Eggermann 13 Epigenetics and Atherosclerosis Einari Aavik, Mikko P. Turunen, and Seppo Ylä-Herttuala 14 Microbe-Induced Epigenetic Alterations Hans Helmut Niller, Ferenc Banati, Eva Ay, and Janos Minarovits Index
11 Contributors Einari Aavik, PhD Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland Christian Arsov, MD Department of Urology, University Hospital, Duesseldorf, Germany Eva Ay Microbiological Research Group, National Center for Epidemiology, Budapest, Hungary Esteban Ballestar, PhD Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L Hospitalet de Llobregat, Barcelona, Spain Ferenc Banati, PhD Microbiological Research Group, National Center for Epidemiology, Budapest, Hungary Gaston Calfa, PhD Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA Maurizio D Esposito, PhD Institute of Genetics and Biophysics Adriano Buzzati- Traverso CNR, Naples, Italy Lorenzo de la Rica, MSc Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L Hospitalet de Llobregat, Barcelona, Spain Walter Doerfler, MD Institute for Virology, Erlangen University, Erlangen, Germany Institute of Genetics, University of Cologne, Cologne, Germany Thomas Eggermann, PhD Institut für Humangenetik, RWTH Aachen, Aachen, Germany Sole Gatto Institute of Genetics and Biophysics Adriano Buzzati-Traverso CNR, Naples, Italy xi
12 xii Contributors Wolfgang Goering, PhD Department of Urology, Heinrich Heine University, Duesseldorf, Germany József Haller, PhD, DSc Department of Behavioural Neurobiology, Laboratory of Behavioural and Stress Studies, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary András Kádár, MD Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA Barbara Klausz Department of Behavioural Neurobiology, Laboratory of Behavioural and Stress Studies, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Maria R. Matarazzo, PhD Institute of Genetics and Biophysics Adriano Buzzati-Traverso CNR, Naples, Italy Janos Minarovits, MD, MSc Microbiological Research Group, National Center for Epidemiology, Budapest, Hungary Hans Helmut Niller, MD Institute for Medical Microbiology and Hygiene University of Regensburg, Regensburg, Germany Alan K. Percy, MD Departments of Pediatrics, Neurology, and Genetics, Civitan International Research Center, Birmingham, AL, USA Lucas Pozzo-Miller, PhD Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA Tibor A. Rauch, PhD Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA Wolfgang A. Schulz, PhD Department of Urology, Heinrich Heine University, Duesseldorf, Germany Amanda Ewart Toland, PhD Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA Áron Tulogdi Department of Behavioural Neurobiology, Laboratory of Behavioural and Stress Studies, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Mikko P. Turunen, PhD Ark Therapeutics, Kuopio, Finland John K. Wiencke, PhD Department of Neurological Surgery and Epidemiology, University of California San Francisco, Helen Diller Family Cancer Center, San Francisco, CA, USA
13 Contributors xiii Seppo Ylä-Herttuala, PhD, MD, FESC Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland Dóra Zelena, MD, PhD Department of Behavioural Neurobiology, Laboratory of Behavioural and Stress Studies, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
14
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