Cardiac and Vascular Biology Editor-in-chief: Markus Hecker Johannes Backs Timothy A. McKinsey Editors Epigenetics in Cardiac Disease Cardiac and Vascular Biology Editor-in-chief: Markus Hecker Inst. of Physiology & Pathophysiology , Heidelberg University , Heidelberg , Germany Series Editors: Johannes Backs Department of Molecular Cardiology and Epigenetics , Heidelberg University , Heidelberg , Germany Marc Freichel Institute of Pharmacology , Heidelberg University , Heidelberg , Germany Thomas Korff Inst. of Physiology & Pathophysiology , Heidelberg University , Heidelberg , Germany Dierk Thomas Department of Internal Medicine III , Heidelberg University Hospital , Heidelberg , Germany The book series gives an overview on all aspects of state-of-the-art research on the cardiovascular system in health and disease. Basic research aspects of medically relevant topics are covered and the latest advances and methods covering diverse disciplines as epigenetics, genetics, mechanobiology, platelet research or stem cell biology are featured. The book series is intended for researchers, experts and gradu- ates, both basic and clinically oriented, that look for a carefully selected collection of high quality review articles on their respective fi eld of expertise. More information about this series at h ttp://www.springer.com/series/13128 Johannes Backs (cid:129) Timothy A. McKinsey Editors Epigenetics in Cardiac Disease Editors Johannes Backs Timothy A. McKinsey Department of Molecular Department of Medicine Cardiology and Epigenetics Division of Cardiology University of Heidelberg University of Colorado Denver Heidelberg Aurora Germany Colorado USA ISSN 2509-7830 ISSN 2509-7849 (electronic) Cardiac and Vascular Biology ISBN 978-3-319-41455-3 ISBN 978-3-319-41457-7 (eBook) DOI 10.1007/978-3-319-41457-7 Library of Congress Control Number: 2016956704 © Springer International Publishing Switzerland 2016 T his work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi 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. T he use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. T he publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is Gewerbestrasse 11, 6330 Cham, Switzerland Pref ace Cardiovascular disease is the leading cause of death worldwide. This book focuses on heart muscle disease, with an emphasis on heart failure, which is a syndrome defi ned by the heart’s inability to adequately pump blood to supply the body’s needs. Risk factors for the development of heart failure include coronary artery disease (CAD), high blood pressure, diabetes, and aging. Based on current guide- lines, most patients with heart failure are treated with three classes of drugs: β-blockers, drugs targeting the angiotensin II type-I receptor (ACE inhibitors or ARBs), and a mineralocorticoid antagonist. Collectively referred to as neurohor- monal blockade, this treatment regimen has clearly been shown to improve out- comes in heart failure patients. Furthermore, LCZ696, which is a dual angiotensin receptor blocker/neprilysin inhibitor, was recently found to be effi cacious in a clini- cal trial with heart failure patients. Indeed, the primary outcome of cardiovascular death or a fi rst hospitalization for heart failure occurred in 21.8 % patients treated with LCZ696, compared with 26.5 % of patients in the control treatment arm. While these fi ndings are encouraging, they also serve to illustrate that disease progression persists in many patients treated with the full armamentarium of heart failure drugs, including LCZ696. Thus, heart failure remains a major unmet medical need, and the elucidation of novel mechanisms involved in heart failure pathogenesis holds prom- ise for identifying new therapies for this prevalent and deadly syndrome. This book focuses on the role of epigenetics and chromatin remodeling for heart muscle disease. T he basic unit of chromatin is the nucleosome, which is a histone octamer wrapped in a 147-bp stretch of DNA. Modifi cations of nucleosomal DNA or pro- tein, without changes to the underlying nucleotide sequence, can have a profound effect on gene expression. This mode of gene regulation is referred to as epi- genetics. Based on data that are extensively reviewed in this book, we strongly believe that epigenetics represents a crucial, untapped reservoir for heart failure drug discovery and development. Our position is founded on the fact that epigen- etic regulators function as “nodal” points that integrate upstream signals to convey a common pathway for heart failure pathogenesis. Furthermore, many epigenetic regulators have proven to be ideally suited for small molecule-mediated manipula- tion, and a multitude of epigenetic therapies are approved or are being tested for the treatment of noncardiac indications in humans, establishing the feasibility of this approach. v vi Preface T he book covers fi ndings that validate roles for fundamental epigenetic pro- cesses (e.g., DNA methylation, histone acetylation, and histone methylation) in the control of heart failure. Furthermore, several chapters delve into chromatin signal- ing and nongenomic roles for classical epigenetic effectors. For example, it is now clear that histone deacetylases (HDACs) have many nonhistone substrates, and deacetylation of these substrates has profound effects on fundamental cellular pro- cesses other than transcription. Finally, the book concludes with a discussion of a newly emerging class of epigenetic regulators referred to as long nonprotein-coding RNAs (lncRNAs), which infl uence gene expression by altering chromatin organiza- tion and function. We are grateful to the authors of the outstanding chapters in this book. The book illustrates that work done by the fi eld over the last 15 years has signifi cantly advanced our understanding of the role of epigenetics in the pathogenesis of heart failure. However, we expect the next 10 years to be a truly golden era for researchers in this fi eld, where fundamental mechanistic studies are bridged with state-of-the- art drug discovery approaches to yield innovative ‘epigenetic therapies’ to combat the worldwide epidemic of heart failure. Timothy A. McKinsey and Johannes Backs Contents 1 Epigenetics: Chromatin Organization and Function . . . . . . . . . . . . . 1 Genevieve P. Delcuve , Dilshad H. Khan , Vichithra R. B. Liyanage , Sanzida Jahan , Mojgan Rastegar , Lorrie A. Kirshenbaum , and James R. Davie 2 Epigenome Dynamics and Reader Proteins in Cardiomyocyte Development and Heart Failure . . . . . . . . . . . . . . . 37 Lutz Hein 3 Epigenetic Regulations in Cardiac Development . . . . . . . . . . . . . . . . . 53 Mei Xin and Kunhua Song 4 DNA Methylation in Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Justus Stenzig and Roger S-Y Foo 5 Chromatin Remodeling in Heart Failure . . . . . . . . . . . . . . . . . . . . . . . 103 Pei Han , Jin Yang , Ching Shang , and Ching-Pin Chang 6 Histone Methylation in Heart Development and Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Zhi-Ping Liu 7 The Lysine Acetyltransferases in Cardiovascular Disease . . . . . . . . . 147 Nanette H. Bishopric 8 HDAC Signaling Networks in Heart Failure . . . . . . . . . . . . . . . . . . . . 191 Mariya Kronlage , Hugo A. Katus , and Johannes Backs 9 Epigenetic and Nongenomic Roles for Histone Deacetylases in Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Weston W. Blakeslee , Philip D. Tatman , and Timothy A. McKinsey 10 Cardiac Autophagy and Its Regulation by Reversible Protein Acetylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Min Xie and Joseph A. Hill 11 Sirtuins as Regulators of Cardiac Hypertrophy and Heart Failure . . . 263 Sadhana Samant and Mahesh P. Gupta vii viii Contents 12 BET Bromodomains and P-TEFb in Cardiac Transcription and Heart Failure Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Priti Anand , Amir Munir , and Saptarsi M. Haldar 13 Long Noncoding RNAs in Heart Disease . . . . . . . . . . . . . . . . . . . . . . . 297 Constantin Kühl and Norbert Frey 1 Epigenetics: Chromatin Organization and Function Genevieve P. Delcuve , Dilshad H. Khan , Vichithra R. B. Liyanage , Sanzida Jahan , Mojgan Rastegar , Lorrie A. Kirshenbaum , and James R. Davie Contents 1.1 Basic and Higher-Order Levels of Chromatin Structure 2 1.2 Nucleosome Dynamics and Gene Regulation 5 1.3 Histone PTMs 6 1.3.1 Histone Acetylation 8 1.3.2 Histone Phosphorylation 10 1.3.3 Histone Methylation 10 1.3.4 Other PTMs of Histones 12 1.4 DNA Methylation 13 1.4.1 CpG Methylation 14 1.4.2 CpH Methylation 15 1.4.3 DNA Methylation-Related Regulatory Proteins 15 1.5 Nucleosomes, Transcription and RNA Splicing 16 1.6 Enhancers 18 1.7 Epigenetics and Metabolism 19 1.8 ncRNA and Epigenetic Modifi ers 19 1.9 Concluding Remarks 20 References 22 G. P. Delcuve (cid:129) D. H. Khan (cid:129) S. Jahan (cid:129) M. Rastegar Department of Biochemistry and Medical Genetics , University of Manitoba , Winnipeg, MB R3E 0J9 , Canada Manitoba Institute of Cell Biology , University of Manitoba , Winnipeg , MB R3E 0J9 , Canada V. R. B. Liyanage Department of Biochemistry and Medical Genetics , University of Manitoba , Winnipeg, MB R3E 0J9 , Canada L. A. Kirshenbaum Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba , Winnipeg , MB R3E 0J9 , Canada J. R. Davie (*) Manitoba Institute of Cell Biology , University of Manitoba , Winnipeg , MB R3E 0J9 , Canada e-mail: [email protected] © Springer International Publishing Switzerland 2016 1 J. Backs, T.A. McKinsey (eds.), Epigenetics in Cardiac Disease, Cardiac and Vascular Biology, DOI 10.1007/978-3-319-41457-7_1