Chromatin Regulation and Dynamics

475 Pages·2016·16.025 MB·English

by  Anita Göndör

Chromatin Regulation
and Dynamics
Edited by
Anita Göndör
Department of Microbiology, Tumor and Cell Biology,
Karolinska Institutet, Stockholm, Sweden
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List of Contributors
P. Agarwal Department of Molecular Biosciences, Institute for Molecular and
Cellular Biology, University of Texas at Austin, Austin, TX, United States
D. Bade Hubrecht Institute, Uppsalalaan, Utrecht, The Netherlands
A.J. Bannister The Gurdon Institute, University of Cambridge, Cambridge,
United Kingdom
W.J. Belden Department of Animal Sciences, School of Environmental and
Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick,
NJ, United States
M. Berdasco Cancer Epigenetics Group, Cancer Epigenetics and Biology
Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona,
Catalonia, Spain
C. Brossas Institut Jacques–Monod, CNRS, Paris Diderot University, Paris,
France
S. Cacchione Department of Biology and Biotechnology, Istituto Pasteur
Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
G. Castelo-Branco Laboratory of Molecular Neurobiology, Department
of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm,
Sweden
A. Cicconi Department of Biology and Biotechnology, Istituto Pasteur Italia -
Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
D. Doenecke Institute for Molecular Biology, University of Göttingen,
Göttingen, Lower Saxony, Germany
M.E. Donohoe Burke Medical Research Institute, White Plains; Department
of Neuroscience, Department of Cell and Developmental Biology, Brain Mind
Research Institute, Weill Cornell Medical College, New York, NY, United States
B. Duriez Institut Jacques–Monod, CNRS, Paris Diderot University, Paris,
France
S. Erhardt ZMBH, DKFZ-ZMBH-Alliance; Cell Networks Excellence Cluster,
University of Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany
xvii
xviii List of Contributors
M. Esteller Cancer Epigenetics Group, Cancer Epigenetics and Biology
Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL);
Department of Physiological Sciences II, School of Medicine, University of
Barcelona; Catalan Institution for Research and Advanced Studies (ICREA),
Barcelona, Catalonia, Spain
A.M. Falcão Laboratory of Molecular Neurobiology, Department of Medical
Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
A. Fiszbein Institute of Physiology, Molecular Biology and Neurosciences
(IFIBYNE-CONICET) and Department of Physiology, Molecular and Cell,
Faculty of Natural Sciences, University of Buenos Aires, Ciudad Universitaria,
Buenos Aires, Argentina
A. Galati Department of Biology and Biotechnology, Istituto Pasteur Italia -
Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
M.A. Godoy Herz Institute of Physiology, Molecular Biology and
Neurosciences (IFIBYNE-CONICET) and Department of Physiology, Molecular
and Cell, Faculty of Natural Sciences, University of Buenos Aires, Ciudad
Universitaria, Buenos Aires, Argentina
L.I. Gomez Acuña Institute of Physiology, Molecular Biology and
Neurosciences (IFIBYNE-CONICET) and Department of Physiology, Molecular
and Cell, Faculty of Natural Sciences, University of Buenos Aires, Ciudad
Universitaria, Buenos Aires, Argentina
A. Göndör Department of Microbiology, Tumor and Cell Biology, Karolinska
Institutet, Stockholm, Sweden
A.R. Kornblihtt Institute of Physiology, Molecular Biology and Neurosciences
(IFIBYNE-CONICET) and Department of Physiology, Molecular and Cell,
Faculty of Natural Sciences, University of Buenos Aires, Ciudad Universitaria,
Buenos Aires, Argentina
A. Lennartsson Department of Biosciences and Nutrition, Karolinska
Institutet, Huddinge, Sweden
M. Lezzerini Integrated Cardio Metabolic Centre, Department of Medicine,
Karolinska Institutet, Huddinge, Sweden
S.J. Linder Program in Biological and Biomedical Sciences, Harvard Medical
School; Massachusetts General Hospital Cancer Center, Boston, MA, United
States
R. Margueron Curie Institute; INSERM; CNRS, Paris, France
M. Martino Department of Microbiology, Tumor and Cell Biology, Karolinska
Institutet, Stockholm, Sweden
E. Micheli Department of Biology and Biotechnology, Istituto Pasteur Italia -
Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
L. Millán-Ariño Department of Medicine, Karolinska University Hospital,
Stockholm, Sweden
K.M. Miller Department of Molecular Biosciences, Institute for Molecular
and Cellular Biology, University of Texas at Austin, Austin, TX, United States
List of Contributors xix
R. Mostoslavsky Program in Biological and Biomedical Sciences, Harvard
Medical School; Massachusetts General Hospital Cancer Center, Boston, MA,
United States
A-.K. Östlund Farrants Department of Molecular Biosciences, The Wenner–
Gren Institute, Stockholm University, Stockholm, Sweden
M-.N. Prioleau Institut Jacques–Monod, CNRS, Paris Diderot University,
Paris, France
C.G. Riedel Integrated Cardio Metabolic Centre, Department of Medicine,
Karolinska Institutet, Huddinge, Sweden
B.A. Scholz Department of Microbiology, Tumor and Cell Biology, Karolinska
Institutet, Stockholm, Sweden
I. Tzelepis Department of Microbiology, Tumor and Cell Biology, Karolinska
Institutet, Stockholm, Sweden
A-.L. Valton Institut Jacques–Monod, CNRS, Paris Diderot University,
Paris, France; Program in Systems Biology, Department of Biochemistry
and Molecular Pharmacology, University of Massachusetts Medical School,
University of Massachusetts, Worcester, MA, United States
M. Wassef Curie Institute; INSERM; CNRS, Paris, France
Preface
Chromatin research is a quickly developing field, which is in the center of cell
differentiation, development, stem cell biology and aging. Moreover, almost
all complex diseases display chromatin changes, many of which have proved to
be causally linked to the disease, or to have diagnostic and/or prognostic val-
ues. This book provides a comprehensive overview on the most recent scientif-
ic achievements of chromatin-based processes, and is divided into 17 chapters
that build on each other, but can also be consulted independently.
The first 11 chapters cover the basic principles of chromatin regulation and
introduce the reader to the language of chromatin marks, their dynamics
throughout the cell cycle and their context-dependent functions in various nu-
clear processes including transcriptional regulation, DNA replication, splicing,
DNA repair, and ribosomal RNA transcription. These chapters discuss novel
principles with a cross-disciplinary perspective, explain chromatin-based pro-
cesses in the context of development, and present links to numerous human
diseases.
Building on the information introduced in the first 11 chapters of the book,
Chapters 12–14 discuss the mechanism by which heritable chromatin states
contribute to the function of specialized regions of the genome, such as telo-
meres and centromeres, as well as to the formation of repressed states on the
inactive X chromosome; processes that are all central to development and of-
ten deregulated in diseases.
As the activity of chromatin-modifying enzymes is influenced by the levels of
intermediary metabolites that act as cofactors or substrates for the enzymatic
reactions, Chapters 15 and 16 integrate various aspects of chromatin biology
with cellular metabolic states. Chromatin states as well as many of the cellular
metabolic pathways that influence chromatin modifiers are under the regula-
tion of circadian clocks. Circadian chromatin transitions are, in turn, central in
regulating the oscillating expression of gene products that control metabolism,
establishing a two-way relationship between daily oscillations in metabolic
processes and chromatin states. In line with the role of circadian regulation in
xxi
xxii Preface
adaptation to changes in the environment, deregulation of circadian rhythm
predisposes to a wide range of complex diseases, such as metabolic and psychi-
atric disorders, as well as cancer.
The recent years have witnessed an explosion of research suggesting that de-
regulated chromatin states are central to tumor development. Unstable chro-
matin states in tumor cells have thus been suggested to maintain phenotypic
heterogeneity and plasticity within the tumor tissue, enabling the selection of
the fittest clones under continuously changing selective pressure, and thereby
promoting tumor evolution. Chapter 17 thus explores how chromatin states
regulate cellular phenotypic plasticity in health, aging and diseases, such as
cancer. Interestingly, the stability of chromatin states and their role in the
maintenance of cellular phenotypes in health and disease are influenced by the
three-dimensional organization of the genome within the nuclear space. Intro-
duced already in Chapter 1, several chapters of this book discuss how spatial
compartmentalization of nuclear functions and dynamic physical interactions
between distant regulatory elements affect chromatin states, transcription, rep-
lication, and DNA repair. Chapter 17 provides, moreover, an overview of these
features and presents novel hypotheses on how deregulated three-dimensional
nuclear architecture and genome organization might contribute to the emer-
gence of major tumor hallmarks, such as increased phenotypic plasticity.
Taken together, the chapters of the book are written by prominent experts in
the field with the ambition to integrate a broad range of topics on chromatin
research to promote crosstalk between basic sciences and their applications in
medicine. The book is thus targeted toward biological and medical scientists,
as well as undergraduate and PhD students in biology or medicine with an
interest in chromatin regulation and in how chromatin-mediated processes
contribute to development, aging and complex diseases.
Finally, I would like to express my gratitude to all the contributors and
coauthors whose work has made it possible to bring this book into existence. I
would like to thank professor Trygve Tollefsbol for organizing the Translational
Epigenetics series and inviting me to participate in this ambition. Many thanks
are given to Catherine Van Der Laan, Lisa Eppich, and the production team at
Elsevier for their dedication, encouragement, and assistance in printing this
book. Appreciation and thanks are also given to the anonymous reviewers of
the chapters for their valuable comments. I would like to recognize the contri-
bution of my group members and colleagues, especially Drs Barbara A. Scholz
and Lluís Millan-Ariño, as well as Mirco Martino and Ilias Tzelepis. Finally, I
thank my family for their support and patience during the preparation of this
book.
Anita Göndör
CHAPTER 1
A Brief Introduction to Chromatin
Regulation and Dynamics
I. Tzelepisa, M. Martinoa, A. Göndör
Department of Microbiology, Tumor and Cell Biology,
Karolinska Institutet, Stockholm, Sweden
1.1 INTRODUCTION TO BASIC CONCEPTS
CONTENTS
OF CHROMATIN REGULATION
1.1 Introduction
The distinct cell types of a multicellular organism have stable, characteristic to Basic Concepts
phenotypes and perform specialized functions; despite that they contain, with of Chromatin
few exceptions, the very same DNA sequence. The existence of a system that Regulation .....................1
regulates the cell type–specific use of the genetic material and provides cellu- 1.2 Epigenetic
lar memories of gene expression patterns over time has been long recognized Phenomena: Heritability
of Chromatin States
[1,2]. At the same time, such a mechanism has to display a considerable level
During Cell Division ......3
of flexibility and responsiveness to environmental cues, enabling the cells to
1.2.1 Inheritance of Stable,
change their phenotypes during adaptive responses [1,2]. The complexity of
Cell Type–Specific Gene
the molecular mechanism that regulates when and how genes should be ex- Expression Patterns ...............3
pressed has only recently been elucidated, long after the first description of 1.2.2 Genomic Imprinting ......6
the biological processes and phenotypes they regulate. In the nucleus DNA 1.2.3 Random Monoallelic
Gene Expression .....................7
is thus organized in chromatin structure that includes an array of histone
1.2.4 Other Epigenetic
and nonhistone proteins, their posttranslational modifications (PTMs), RNA
Phenomena .............................8
components, as well as DNA modifications [1,2]. Chromatin regulates not
1.3 Reprogramming
only the efficient packaging of the genome into the nuclear space, but also
of Epigenetic States
influences the accessibility of the underlying DNA to trans-acting factors, and During Development
provides a platform for the regulated recruitment of enzymatic functions and in Diseases .............8
and proteins that orchestrate various genomic functions [1,2]. Chromatin thus 1.3.1 Reprogramming
of Epigenetic Marks During
plays essential roles in all nuclear processes templated by the genetic material,
Early Development ..................9
including transcription (Chapters 1–6, 8–10), RNA splicing (Chapter 8), DNA
1.3.2 Epigenetic
replication (Chapters 5–6), and DNA repair (Chapter 11), with far-reaching Reprogramming in Tumor
consequences on human health [1,2]. It is not surprising therefore that chro- Development .........................10
matin research has had an increasing influence on a wide range of research 1.4 Early Period
of Chromatin
Research .....................11
(Continued)
aThese authors contributed equally to the manuscript. 1
Chromatin Regulation and Dynamics. http://dx.doi.org/10.1016/B978-0-12-803395-1.00001-0
Copyright © 2017 Elsevier Inc. All rights reserved.
2 CHAPTER 1: A Brief Introduction to Chromatin Regulation and Dynamics
1.5 Discovery fields, such as developmental biology, aging, and various monogenic, as well
of the Nucleosome as complex diseases.
and Nucleosome
Positioning ..................11 Chromatin marks can be divided into open, transcriptionally permissive, eu-
chromatin modifications and compact, repressive, heterochromatin marks
1.6 Histone
Modifications: Discovery [1,2]. The identity and function of the various histone PTMs and DNA modifi-
and Function ...............12 cations is discussed in details in Chapters 2–3. An important feature of histone
1.6.1 The Language modifications is their reversible nature, which reflects that these PTMs are the
of Histone Modifications .......13 result of opposing enzymatic activities [1,2]. Even modifications of the DNA,
1.7 Discovery of such as cytosine (C) methylation, are reversible, although active demethylation
DNA Methylation: requires collaboration between multiple enzymes and DNA repair factors [1,2]
Functions and Cross (see also Chapter 3). A key question in chromatin biology is therefore how
Talk With Histone
chromatin-modifying activities are targeted to specific sites of the genome
Modifications ...............14
to maintain gene expression patterns or bring about a change in the expres-
1.7.1 Discovery of DNA
Methylation ...........................14 sion of specific genes. Although not completely understood, this process is
1.7.2 DNA Methylation regulated by interactions between chromatin modifiers and sequence-specific,
in Tumor Development .........15 DNA-binding proteins/transcription factors or other existing chromatin com-
1.7.3 Cross Talk Between
ponents [3]. Environmental cues that regulate the expression and/or function
DNA Methylation and
of transcription factors or directly modify chromatin and chromatin modifiers
Histone Modifications ...........16
play thus important roles in the regulation of chromatin states and the expres-
1.8 Replication
sivity of the genome [3,4].
Timing: Potential
Vehicle for Epigenetic A subset of the dynamic chromatin modifications have been shown to be heri-
Inheritance and
table during mitosis and sometimes even during meiosis [1,2]. These heritable
Reprogramming ..........17
chromatin marks are called epigenetic marks, which can propagate the effects
1.9 Chromatin of transient environmental signals, developmental cues and cellular metabolic
Folding in 3D: Basic
states on gene expression long after the exposure to the initial stimulus [1,2].
Principles of Genome
Several mechanisms have evolved to enable epigenetic modifications to be cop-
Organization ................18
ied and maintained during cell divisions, thereby providing cellular memories
1.9.1 Cross Talk Between
Regulatory Elements ............19 that maintain specific states of differentiation [1,2]. Finally, even heritable epi-
1.9.2 Technical Innovations genetic states can be altered at a genome-wide level during certain stages of de-
to Detect 3D Genome velopment, upon specific signals and in diseases, as discussed further. One of
Organization ..........................19
the enigmas of chromatin regulation is how two opposing features, namely the
1.9.3 Compartmentalization
stability and plasticity of chromatin states, is fine-tuned in response to internal
of Nuclear Functions ............22
and external signals. Regulation of chromatin dynamics is thus central to our
1.10 Signal Integration
understanding of the mechanisms that balance on one hand, the robustness
at the Level
of cellular phenotypes against perturbations and on the other hand, adaptive
of Chromatin ...............23
phenotypic plasticity [4,5] (discussed in Chapter 17).
1.11 Outlook ................25
In this chapter we will start by presenting the early experiments that high-
Abbreviations ..............26
lighted the existence of cellular memories of gene expression patterns over
Acknowledgments ......27 time, and inspired investigations to uncover the molecular mechanism of
Conflict of Interest ......27 epigenetic inheritance. As mentioned earlier, it has long been recognized that
even these heritable cellular states can be reprogrammed during certain de-
References ..................27
velopmental windows and in diseases. We will thus briefly present the major
1.2 Epigenetic Phenomena: Heritability of Chromatin States During Cell Division 3
reprogramming events that take place during development and in cancer. We
will then provide an overview of the history of chromatin research that eventu-
ally uncovered the link between cellular memories and chromatin states. As
all chromatin-templated functions take place in the three-dimensional (3D)
space of the nucleus, we will introduce the basic concepts of 3D genome orga-
nization and its consequences on genomic functions, such as transcription and
replication. We will end by a modern definition of chromatin regulation that
views chromatin states as platforms for the integration of internal and external
cues over time during development and during adaptation to environmental
signals, as well as in diseases.
1.2 EPIGENETIC PHENOMENA: HERITABILITY
OF CHROMATIN STATES DURING CELL DIVISION
The term “epigenetic” has been introduction by Conrad Waddington in 1942
[2,6,7] (Fig. 1.1), and has undergone many different interpretations since then.
Waddington used it to describe all the regulated processes that lead to the
development of the adult organism from the zygote, and suggested that this
process required interactions between the genotype, epigenotype, and the
environment [7]. In his famous metaphor (Fig. 1.2A), he thus described cell
differentiation as a ball rolling down on the “epigenetic landscape” toward
well-defined valleys representing mature cell states. In this representation,
“canalization” of the rolling ball by the valleys toward specific directions, or
in other words “buffering,” refers to the maintenance of stable developmental
outcomes despite environmental perturbations [7]. On the contrary, “devel-
opmental plasticity” refers to the generation of multiple cellular phenotypes
from the same genotype. Hence, the concept of a regulatory layer that interacts
with both the genotype and the environment has been proposed before the
discovery of the chromatin-based mechanisms of gene regulation [2]. A more
modern use of epigenetics builds on the knowledge about the existence of dy-
namic and heritable chromatin modifications, and was proposed by Riggs and
Porter in 1996 to include the “mitotically and/or meiotically stable changes in
gene function that cannot be explained by changes in the DNA sequence” [8].
Epigenetic phenomena thus refer to the cellular memories of chromatin states,
which can be surprisingly stable during the lifetime of the organism, some-
times even in between generations. These epigenetic features are thus essential
for the stable maintenance of cell type–specific gene expression patterns and
normal development [2].
1.2.1 Inheritance of Stable, Cell Type–Specific Gene
Expression Patterns
Early experiments providing evidence for the existence of stable gene express ion
patterns through cell divisions were performed already in the 1960s. Hadorn