See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/303833818

Chromatin Remodeling

Chapter · June 2016

DOI: 10.1007/978-94-017-7741-4_11

CITATIONS READS

0 2,833

2 authors, including:

Ferdinand Molnár
Nazarbayev University
155 PUBLICATIONS 1,508 CITATIONS

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Human epigenomics View project

Generative ML and DTA prediction View project

All content following this page was uploaded by Ferdinand Molnár on 17 October 2017.

The user has requested enhancement of the downloaded file.

Carsten Carlberg · Ferdinand Molnár

Mechanisms
of Gene
Regulation
Second Edition
Mechanisms of Gene Regulation
Carsten Carlberg • Ferdinand Molnár

Mechanisms of Gene
Regulation
Second Edition
Carsten Carlberg Ferdinand Molnár
Institute of Biomedicine, Institute of Biopharmacy,
School of Medicine School of Pharmacy
University of Eastern Finland University of Eastern Finland
Kuopio, Finland Kuopio, Finland

ISBN 978-94-017-7740-7 ISBN 978-94-017-7741-4 (eBook)

DOI 10.1007/978-94-017-7741-4

Library of Congress Control Number: 2016942770

© Springer Science+Business Media Dordrecht 2014, 2016

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
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 transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the 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 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 Science+Business Media B.V. Dordrecht
Preface to the Second Edition

Due on the widespread use of next-generation sequencing technologies and system-

atic approaches of large research consortia, such as ENCODE, FANTOM5, and
Roadmap Epigenomics, the field of gene regulation and epigenomics undergoes
rapid development. The progress in the topic as well as the success of the first edi-
tion of this textbook stimulated us to prepare already after 2.5 years a new version.
We carefully revised and updated all text and references and provide now all
figures in color. We are grateful to Prof. Changwon Kang (Korea Advanced Institute
of Science) and René Tinschert (University of Saarland, Germany) for notifying us
about typos and minor inconsistencies.
We hope the readers will continue enjoying our book and share our enthusiasm
about the mechanisms of gene regulation.

Kuopio, Finland Carsten Carlberg

February 2016 Ferdinand Molnár

v
Preface to the First Edition

This textbook describes the fascinating area of eukaryotic gene regulation. Gene
expression is shaping the phenotype of cells and tissues; its regulation therefore is
the essential fundamental aspect of nearly all processes in physiology, both in health
and in disease. For this reason not only biologists and biochemists should be aware
of the concepts of gene regulation, but all students of biomedical areas would ben-
efit from being introduced into this topic, in order to have a good basis for their
specialized disciplines. A complete understanding of transcription factors and the
processes that alter their activity is a fundamental goal of modern life science
research.
The availability of the whole human genome sequence (and that of other eukary-
otic genomes) and the consequent development of next-generation sequencing tech-
nologies have significantly changed nearly all areas of bioscience. For example, the
genome-wide location of histone modifications and transcription factor binding
sites, such as provided by the ENCODE consortium, has largely improved our
understanding of gene regulation. Therefore, the focus of this book is the descrip-
tion of the post-genome understanding of gene regulation.
The purpose of this book is to provide in a condensed form an overview on the
present understanding of the mechanisms of gene regulation. We are not aiming to
compete with more comprehensive books, such as the legendary “Genes” of Ben
Lewin, but rather will focus on the essentials. In order to facilitate the latter, we
favor a high figure-to-text ratio following the rule “a picture tells more than thou-
sand words”.
The content of the book is based on the lecture course “Mechanism of Gene
Regulation” that is given by one of us (C. Carlberg) continuously since 2001 at the
University of Eastern Finland in Kuopio. The book is sub-divided into 4 sections
and 13 chapters. Following the Introduction there are 3 sections that take a view on
gene regulation from the perspective of transcription factors, chromatin and non-
coding RNA, respectively. The lecture course is primarily designed for Master level
students of Biosciences, but is also frequented by students of other biomedical dis-
ciplines and by PhD students. The course and hence this textbook has four major
learning objectives. Students should:

vii
viii Preface to the First Edition

1. Have detailed understanding of the structure of genes, chromatin organization,

transcription factors and their regulatory mechanisms.
2. Recognize the key components, mechanisms and processes in gene expression
and the multiple layers of its regulatory complexity.
3. Show the ability to analyze transcription factors, their co-regulators and non-
coding RNA concerning there expression and genome-wide effects, i.e., to judge
their impact on the complex regulation of eukaryotic genes.
4. Apply knowledge in gene regulation in designing, performing and analyzing
respective experiments, such as quantitative PCR, RNA-seq and ChIP-seq.
We hope the readers will enjoy this rather visual book and get as enthusiastic
about the topic of gene regulation as the authors are.

Kuopio, Finland Carsten Carlberg

August 2013 Ferdinand Molnár
Contents

Part I Introduction
1 Overview: What Is Gene Expression? .................................................. 3
1.1 The Central Dogma of Molecular Biology .................................... 4
1.2 Transcriptional Complexity of Genes ............................................ 7
1.3 Elements of Transcriptional Regulation......................................... 9
1.4 The Role of Chromatin Activity in Gene Regulation .................... 11
1.5 Gene Expression Programs ............................................................ 13
Additional Reading ................................................................................... 16
2 The Impact of Chromatin....................................................................... 17
2.1 Eu- and Heterochromatin ............................................................... 18
2.2 Nucleosomes .................................................................................. 20
2.3 Histone Modifications in Chromatin Opening and Closing........... 23
2.4 Genomic Effects of Histone Modifications.................................... 25
2.5 Chromatin Architecture.................................................................. 30
2.6 Impact of Epigenetic Signaling in Health and Disease .................. 32
Additional Reading ................................................................................... 34

Part II Transcription Factor View

3 The Basal Transcriptional Machinery .................................................. 37
3.1 The Core Promoter......................................................................... 38
3.2 The TATA Box ............................................................................... 42
3.3 Core Promoter Elements ................................................................ 45
3.4 TFIID as a Paradigm of a Multi-protein Complex......................... 47
3.5 Genome-Wide Approaches on Core Promoter Identification ........ 48
3.6 The Mediator Complex .................................................................. 51
Additional Reading ................................................................................... 55

ix
x Contents

4 Transcription Factors ............................................................................. 57

4.1 Site-Specific Transcription Factors ................................................ 58
4.2 Transcription Factor Domains ....................................................... 59
4.3 Dimeric Transcription Factor Complexes:
The Example of Nuclear Receptor Heterodimers .......................... 62
4.4 Bioinformatic Identification of Transcription
Factor Binding Sites....................................................................... 64
4.5 Transcription Factor Expression Profile ........................................ 67
4.6 Classification of Transcription Factors .......................................... 69
Additional Reading ................................................................................... 73
5 Linking Signal Transduction and Gene Regulation ............................ 75
5.1 Activation of Latent Transcription Factors .................................... 76
5.2 Transcription Factor Networks ...................................................... 78
5.3 Programming Cellular Differentiation
by Transcription Factors ................................................................ 80
5.4 NF-κB Signaling ............................................................................ 83
5.5 Transcription Factors in the Inflammatory Response .................... 87
5.6 Sensing Cellular Stress: The p53 Pathway .................................... 89
Additional Reading ................................................................................... 93
6 Switching Genes On and Off: The Example
of Nuclear Receptors............................................................................... 95
6.1 The Nuclear Receptor Superfamily ............................................... 95
6.2 Molecular Interactions of Nuclear Receptors ................................ 98
6.3 Physiological Role of Nuclear Receptors ...................................... 101
6.4 Nuclear Receptors and Their Ligands............................................ 102
6.5 Interaction of Nuclear Receptors with Co-factors ......................... 105
Additional Reading ................................................................................... 108
7 Mapping the Genome ............................................................................. 109
7.1 Phylogenetic Footprinting.............................................................. 109
7.2 The ENCODE Project .................................................................... 112
7.3 Exploring Data of the ENCODE Project ....................................... 115
7.4 Integrating ChIP-seq Data.............................................................. 116
7.5 Alternative DNA Binding Modes of Transcription Factors ........... 118
7.6 Assigning Transcription Factors to Their Target Genes ................ 120
Additional Reading ................................................................................... 124

Part III Chromatin View

8 Chromatin Modifiers .............................................................................. 129
8.1 The Histone Code Model ............................................................... 130
8.2 Histone Modifying Enzymes ......................................................... 134
8.3 Genome-Wide Analysis of Histone Markers
and Their Modifying Enzymes ...................................................... 138
8.4 Chromatin Modifiers in Disease .................................................... 140
Additional Reading ................................................................................... 144
 Contents xi

9 Genomic Imprinting ............................................................................... 147

9.1 Insulators ........................................................................................ 147
9.2 The Genome Regulator CTCF ....................................................... 149
9.3 Genomic Imprinting ....................................................................... 151
9.4 Models of Insulator Function ......................................................... 154
9.5 Inheritance of CTCF-Mediated Chromatin Structures .................. 155
Additional Reading ................................................................................... 158
10 The Epigenome ........................................................................................ 159
10.1 DNA Methylation........................................................................... 160
10.2 DNA Methylation on the Genome Scale ....................................... 160
10.3 DNA Methylation, Heterochromatin and Gene Silencing ............. 164
10.4 Epigenomics in Health and Disease............................................... 168
Additional Reading ................................................................................... 172
11 Chromatin Remodeling .......................................................................... 173
11.1 The Impact of Chromatin Remodeling .......................................... 174
11.2 ATP-Dependent Remodeling Complexes ...................................... 176
11.3 Nucleosome Positioning at Promoters ........................................... 178
11.4 Pioneer Factors............................................................................... 181
11.5 Transcriptional Dynamics and Noise ............................................. 183
Additional Reading ................................................................................... 186
12 Chromatin Architecture ......................................................................... 187
12.1 Organization of the Nucleus .......................................................... 188
12.2 Larger Order DNA Loop Formation .............................................. 190
12.3 Compartmentalization of Nuclear Processes ................................. 192
12.4 Transcription Factories .................................................................. 193
12.5 Nuclear Position and Disease......................................................... 195
Additional Reading ................................................................................... 196

Part IV Non-coding RNA View

13 Regulatory RNA ...................................................................................... 199
13.1 Non-coding RNAs ......................................................................... 200
13.2 miRNAs and Their Function .......................................................... 201
13.3 Long ncRNA .................................................................................. 205
13.4 eRNAs ............................................................................................ 206
13.5 Gene Regulation by miRNAs and Transcription Factors .............. 208
Additional Reading ................................................................................... 211

View publication stats