Human Epigenomics

"The term epigenetics describes regulatory and information storing mechanisms of specific genes that do not involve any change of their DNA sequence. Epigenetics is closely related to the extensively folded state, in which the genome is packaged, known as chromatin. New genomic tools nowadays allow the genome-wide assessment of, for example, chromatin states and DNA modifications, and led to the discovery of unexpected new epigenetic principles, such as epigenomic memory. This was the start of the field of epigenomics, the relation of which to human health and disease is discussed in this textbook. This book aims to summarize, in a condensed form, the role of epigenomics in defining chromatin states that are representative of active genes (euchromatin) and repressed genes (heterochromatin). Moreover, this book discusses the principles of gene regulation, chromatin stability, genomic imprinting and the reversibility of DNA methylation and histone modifications. This information should enable a better understanding of cell type identities and will provide new directions for studies of, for example, cellular reprograming, the response of chromatin to environmental signals and epigenetic therapies that can improve or restore human health. In order to facilitate the latter, we favor a high figure-to-text ratio following the rule "a picture tells more than thousand words". The content of the book is based on the lecture course "Molecular Medicine and Genetics" that is given by one of us (C. Carlberg) in different forms since 2002 at the University of Eastern Finland in Kuopio. Thematically, this book is located between our textbooks "Mechanisms of Gene Regulation" (ISBN 978-94-017-7741-4) and "Nutrigenomics" (ISBN 978-3-319-30415-1), studying of which may also be interesting to our readers. The book is sub-divided into three sections and 13 chapters. Following the Introduction (section A), section B will explain the molecular basis of epigenomics, while section C will provide examples for the impact of epigenomics in human health and disease. The lecture course is primarily designed for Master level students of biomedicine, but is also frequented by PhD students as well as by students of other bioscience disciplines. Besides its value as a textbook, Human Epigenomics will be a usefull reference for individuals working in biomedicine." -- prové de l'editor Preface 5 Acknowledgements 7 List of Abbreviations 8 Contents 13 About the Authors 16 Part A. Introduction 17 1 What Is Epigenomics? 18 1.1 Chromatin and Gene Expression 19 1.2 The Epigenetic Landscape 23 1.3 Chromatin Organization 25 1.4 Epigenome Marks of Transcriptional Regulation 28 1.5 Impact of Epigenomics on Health and Disease 31 Additional Reading 33 2 Methods and Applications of Epigenomics 34 2.1 Epigenomic Methods 35 2.1.1 Mapping DNA Methylation 36 2.1.2 ChIP-seq 38 2.1.3 Chromatin Accessibility 40 2.1.4 Chromatin Interaction Analyses 41 2.2 Epigenomics Consortia 42 2.2.1 ENCODE 43 2.2.2 FANTOM5 44 2.2.3 Roadmap Epigenomics 46 2.2.4 IHEC 47 2.3 Exploring Epigenomics Data 48 Additional Reading 52 Part B. Molecular Elements of Epigenomics 54 3 The Structure of Chromatin 55 3.1 Central Units of Chromatin: Nucleosomes 55 3.2 Histones and Their Modifications 57 3.3 Histones Variants 58 3.4 Euchromatin and Heterochromatin 61 3.5 Nuclear Architecture 64 3.6 TADs and Chromosome Territories 67 Additional Reading 70 4 DNA Methylation 71 4.1 Cytosines and Their Methylation 72 4.2 DNA Methylation at the Genome Scale 74 4.3 Interaction of Transcription Factors with Methylated DNA 80 4.4 Insulators, CTCF and Imprinting 81 4.5 Link of DNA Methylation to Disease 85 Additional Reading 87 5 The Histone Code 88 5.1 Molecular Principles of the Histone Code 89 5.2 Genome-Wide Interpretation of Histone Modification Patterns 94 5.3 Combinatorial Impact of Histone Modifications 98 Additional Reading 101 6 Chromatin Modifiers 102 6.1 Chromatin Readers 103 6.2 Chromatin Writers 104 6.3 Erasers 108 6.4 Gene Regulation via Chromatin Modifiers 110 6.5 Lysine Demethylase Activity During Cell Cycle Progression 113 Additional Reading 115 7 Chromatin Remodelers and Organizers 116 7.1 Gene Regulation in the Context of Chromatin Structure 117 7.2 Chromatin Remodelers 118 7.3 Chromatin Organization in 3D 124 7.4 Long ncRNAs as Chromatin Organizers 128 Additional Reading 133 Part C. Impact of Epigenomics in Health and Disease 134 8 Embryogenesis and Cellular Differentiation 135 8.1 Chromatin Dynamics During Early Human Development 135 8.2 Reprograming of the Germ Line 140 8.3 Cellular Reprograming to Pluripotency 142 8.4 Chromatin Dynamics During Differentiation 146 8.5 Development and Disease 148 Additional Reading 152 9 Population Epigenomics and Aging 153 9.1 Epigenetic Memory and Transgenerational Inheritance 154 9.2 Population Epigenomics 158 9.3 Epigenomics of Aging 163 Additional Reading 170 10 Cancer Epigenomics 171 10.1 Impact of Epigenetic Mutations in Cancer 172 10.2 Epigenetic Dys-Regulation in Tumorigenesis 174 10.3 Role of Epigenetic Reprograming in Cancer 178 10.4 Epigenetic Mechanisms of the Hallmarks of Cancer 181 10.5 Epigenetic Cancer Therapy 182 10.5.1 KMT Inhibitors 183 10.5.2 KDM Inhibitors 183 10.5.3 KDAC Inhibitors 184 10.5.4 DNMT Inhibitors 184 Additional Reading 186 11 Neuroepigenetics 187 11.1 Epigenetics of Neuronal Development and Memory 188 11.2 MeCP2 and the Rett Syndrome 191 11.3 Epigenetics of Neurodegenerative Diseases 194 Additional Reading 202 12 Epigenomics of Immune Function 203 12.1 Epigenetics of Hematopoietic Differentiation 204 12.2 Role of Epigenetics in Immune Responses 208 12.3 Epigenetics of Immune Diseases 211 Additional Reading 215 13 Nutritional Epigenomics 217 13.1 Epigenetic Mechanisms Linking Metabolites and Gene Transcription 217 13.2 Cell Decisions via the Metabolome-Epigenome Axis 221 13.3 Epigenetic Regulation of Metabolic Tissue Differentiation 224 13.4 Epigenomics of Intergenerational Metabolic Disease 226 Additional Reading 229 Glossary 230 "This textbook aims to describe "the fascinating area of eukaryotic gene regulation for graduate students in all areas of the biomedical sciences. Gene expression is essential in shaping the various phenotypes of cells and tissues and as such, regulation of expression is a fundamental aspect of nearly all processes in physiology, both in healthy and in diseased states. This pivotal role for the regulation of gene expression makes this textbook essential reading from students of all the biomedical sciences in order to be better prepared for their specialized disciplines.A complete understanding of transcription factors and the processes that alter their activity is a major goal of modern life science research. The availability of the whole human genome sequence (and that of other eukaryotic genomes) and the consequent development of next-generation sequencing technologies have significantly changed nearly all areas of the biological sciences. For example, the genome-wide location of histone modifications and transcription factor binding sites, such as provided by the ENCODE consortium, has greatly improved our understanding of gene regulation. Therefore, the focus of this book is the description 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. The authors are not aiming to compete with comprehensive treatises, but rather focus on the essentials. Therefore, the authors have favored a high figure-to-text ratio following the rule which states that "a picture tells more than thousand words."The content of the book is based on the lecture course, which is given by Prof. Carlberg since 2001 at the University of Eastern Finland in Kuopio. The book is subdivided into 4 sections and 13 chapters. Following the Introduction there are three sections, which take a view on gene regulation from the perspective of transcription factors, chromatin and non-coding RNA, respectively. Besides its value as a textbook, "Mechanisms of Gene Regulation "will be a useful reference for individuals working in biomedical laboratories. This textbook aims to describe the fascinating area of eukaryotic gene regulation for graduate students in all areas of the biomedical sciences. Gene expression is essential in shaping the various phenotypes of cells and tissues and as such, regulation of gene expression is a fundamental aspect of nearly all processes in physiology, both in healthy and in diseased states. This pivotal role for the regulation of gene expression makes this textbook essential reading for students of all the biomedical sciences, in order to be better prepared for their specialized disciplines. A complete understanding of transcription factors and the processes that alter their activity is a major goal of modern life science research. The availability of the whole human genome sequence (and that of other eukaryotic genomes) and the consequent development of next-generation sequencing technologies have significantly changed nearly all areas of the biological sciences. For example, the genome-wide location of histone modifications and transcription factor binding sites, such as provided by the ENCODE consortium, has greatly improved our understanding of gene regulation. Therefore, the focus of this book is the description 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. The authors are not aiming to compete with comprehensive treatises, but rather focus on the essentials. Therefore, the authors have favored a high figure-to-text ratio following the rule stating that “a picture tells more than thousand words”. The content of the book is based on the lecture course, which is given by Prof. Carlberg since 2001 at the University of Eastern Finland in Kuopio. The book is subdivided into 4 sections and 13 chapters. Following the Introduction there are three sections, which take a view on gene regulation from the perspective of transcription factors, chromatin and non-coding RNA, respectively. Besides its value as a textbook, Mechanisms of Gene Regulation will be a useful reference for individuals working in biomedical laboratories. This textbook aims to describe the fascinating area of eukaryotic gene regulation for graduate students in all areas of the biomedical sciences. Gene expression is essential in shaping the various phenotypes of cells and tissues and as such, regulation of gene expression is a fundamental aspect of nearly all processes in physiology, both in healthy and in diseased states. This pivotal role for the regulation of gene expression makes this textbook essential reading for students of all the biomedical sciences, in order to be better prepared for their specialized disciplines. A complete understanding of transcription factors and the processes that alter their activity is a major goal of modern life science research. The availability of the whole human genome sequence (and that of other eukaryotic genomes) and the consequent development of next-generation sequencing technologies have significantly changed nearly all areas of the biological sciences. For example, the genome-wide location of histone modifications and transcription factor binding sites, such as provided by the ENCODE consortium, has greatly improved our understanding of gene regulation. Therefore, the focus of this book is the description 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. The authors are not aiming to compete with comprehensive treatises, but rather focus on the essentials. Therefore, the authors have favored a high figure-to-text ratio following the rule stating that 2a picture tells more than thousand words3. The content of the book is based on the lecture course, which is given by Prof. Carlberg since 2001 at the University of Eastern Finland in Kuopio. The book is subdivided into 4 sections and 13 chapters. Following the Introduction there are three sections, which take a view on gene regulation from the perspective of transcription factors, chromatin and non-coding RNA, respectively. Besides its value as a textbook, Mechanisms of Gene Regulation will be a useful reference for individuals working in biomedical laboratories This textbook aims to describe the fascinating area of eukaryotic gene regulation for graduate students in all areas of the biomedical sciences. Gene expression is essential in shaping the various phenotypes of cells and tissues and as such, regulation of expression is a fundamental aspect of nearly all processes in physiology, both in healthy and in diseased states. This pivotal role for the regulation of gene expression makes this textbook essential reading from students of all the biomedical sciences in order to be better prepared for their specialized disciplines. A complete understanding of transcription factors and the processes that alter their activity is a major goal of modern life science research. The availability of the whole human genome sequence (and that of other eukaryotic genomes) and the consequent development of next-generation sequencing technologies have significantly changed nearly all areas of the biological sciences. For example, the genome-wide location of histone modifications and transcription factor biding sites, such as provided by the ENCODE consortium, has greatly improved our understanding of gene regulation. Therefore, the focus of this book is the description 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. The authors are not aiming to compete with comprehensive treatises, but rather focus on the essentials. Therefore, the authors have favored a high figure-to-text ratio following the rule which states that 'a picture tells more than thousand words'. The content of the book is based on the lecture course, which is given by Prof. Carlberg since 2001 at the University of Eastern Finland in Kuopio. The book is subdivided into 4 sections and 13 chapters. Following the Introduction there are three sections, which take a view on gene regulation from the perspective of transcription factors, chromatin and non-coding RNA, respectively. Besides its value as a textbook, Mechanisms of Gene Regulation will be a useful reference for individuals working in biomedical laboratories The fascinating area of Nutrigenomics describes this daily communication between diet, food and nutrients, their metabolites and our genome. This book describes how nutrition shapes human evolution and demonstrates its consequences for our susceptibility to diseases, such as diabetes and atherosclerosis. Inappropriate diet can yield stress for our cells, tissues and organs and then it is often associated with low-grade chronic inflammation. Overnutrition paired with physical inactivity leads to overweight and obesity and results in increased burden for a body that originally was adapted for a life in the savannas of East Africa. Therefore, this textbook does not discuss a theoretical topic in science, but it talks about real life, and our life-long “chat” with diet. We are all food consumers, thus each of us is concerned by the topic of this book and should be aware of its mechanisms. The purpose of this book is to provide an overview on the principles of nutrigenomics and their relation to health or disease. We are not aiming to compete with more comprehensive textbooks on molecular nutrition, evolutionary biology, genomics, gene regulation or metabolic diseases, but rather will focus on the essentials and will combine, in a compact form, elements from different disciplines. In order to facilitate the latter, we favor a high figure-to-text ratio following the rule “a picture tells more than thousand words”. The content of this book is based on the lecture course “Nutrigenomics”, which is held since 2003 once per year by Prof. Carlberg at the University of Eastern Finland in Kuopio. The book is subdivided into three sections and twelve chapters. Following the "Introduction" there are sections on the "Molecular genetic basis" and the "Links to disease", which take a view on nutrigenomics from the perspective of molecular mechanisms or from the causes of metabolic diseases, respectively. Besides its value as a textbook, Nutrigenomics will be a usefull reference for individuals working in biomedicine. The fascinating area of Nutrigenomics describes this daily communication between diet, food and nutrients, their metabolites and our genome. This book describes how nutrition shapes human evolution and demonstrates its consequences for our susceptibility to diseases, such as diabetes and atherosclerosis. Inappropriate diet can yield stress for our cells, tissues and organs and then it is often associated with low-grade chronic inflammation. Overnutrition paired with physical inactivity leads to overweight and obesity and results in increased burden for a body that originally was adapted for a life in the savannas of East Africa. Therefore, this textbook does not discuss a theoretical topic in science, but it talks about real life, and our life-long zchaty with diet. We are all food consumers, thus each of us is concerned by the topic of this book and should be aware of its mechanisms. The purpose of this book is to provide an overview on the principles of nutrigenomics and their relation to health or disease. We are not aiming to compete with more comprehensive textbooks on molecular nutrition, evolutionary biology, genomics, gene regulation or metabolic diseases, but rather will focus on the essentials and will combine, in a compact form, elements from different disciplines. In order to facilitate the latter, we favor a high figure-to-text ratio following the rule za picture tells more than thousand wordsy. The content of this book is based on the lecture course zNutrigenomicsy, which is held since 2003 once per year by Prof. Carlberg at the University of Eastern Finland in Kuopio. The book is subdivided into three sections and twelve chapters. Following the "Introduction" there are sections on the "Molecular genetic basis" and the "Links to disease", which take a view on nutrigenomics from the perspective of molecular mechanisms or from the causes of metabolic diseases, respectively. Besides its value as a textbook, Nutrigenomics will be a usefull reference for individuals working in biomedicine Front Matter ....Pages i-xix Front Matter ....Pages 1-1 What Is Epigenomics? (Carsten Carlberg, Ferdinand Molnár)....Pages 3-18 Methods and Applications of Epigenomics (Carsten Carlberg, Ferdinand Molnár)....Pages 19-38 Front Matter ....Pages 39-39 The Structure of Chromatin (Carsten Carlberg, Ferdinand Molnár)....Pages 41-56 DNA Methylation (Carsten Carlberg, Ferdinand Molnár)....Pages 57-73 The Histone Code (Carsten Carlberg, Ferdinand Molnár)....Pages 75-88 Chromatin Modifiers (Carsten Carlberg, Ferdinand Molnár)....Pages 89-102 Chromatin Remodelers and Organizers (Carsten Carlberg, Ferdinand Molnár)....Pages 103-120 Front Matter ....Pages 121-121 Embryogenesis and Cellular Differentiation (Carsten Carlberg, Ferdinand Molnár)....Pages 123-140 Population Epigenomics and Aging (Carsten Carlberg, Ferdinand Molnár)....Pages 141-158 Cancer Epigenomics (Carsten Carlberg, Ferdinand Molnár)....Pages 159-174 Neuroepigenetics (Carsten Carlberg, Ferdinand Molnár)....Pages 175-190 Epigenomics of Immune Function (Carsten Carlberg, Ferdinand Molnár)....Pages 191-204 Nutritional Epigenomics (Carsten Carlberg, Ferdinand Molnár)....Pages 205-217 Back Matter ....Pages 219-223