Table Of ContentCardiac 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
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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
