Handbook of Epigenetics: The New Molecular and Medical Genetics

Chapter 1 - An Overview of Epigenetics
	Introduction
	Molecular Mechanisms of Epigenetics
	Methods in Epigenetics
	Model Organisms of Epigenetics
	Factors Influencing Epigenetic Changes
	Evolutionary Epigenetics
	Epigenetic Epidemiology
	Epigenetics and Human Disease
	Epigenetic Therapy
	The Future of Epigenetics
	Conclusions
	References
Chapter 2 - Mechanisms of DNA Methylation and Demethylation During Mammalian Development
	Introduction
	DNA Methylation
		Maintenance DNA Methylation
			DNMT1
			UHRF1
		De Novo DNA Methylation
			DNMT3A and DNMT3B
			DNMT3L
	DNA Demethylation
		Passive DNA Demethylation
		Active DNA Demethylation
			TET Proteins
			TET-Dependent Demethylation Pathways
			TET Proteins in Development
	Conclusions
	Glossary
	Abbreviations
	Acknowledgments
	References
Chapter 3 - Mechanisms of Histone Modifications
	Introduction
	Histone Modifications
		Proline Isomerization
		Citrullination
		Ubiquitination
			Role of Histone Ubiquitination in Transcription Regulation
			Role of Histone Ubiquitination in DNA Damage Response
		Sumoylation
		ADP-Ribosylation
		Phosphorylation
			Role of Histone Phosphorylation in Transcription Regulation
			Role of Histone Phosphorylation in DNA Damage Response
		Methylation
			Role of Histone Methylation in Transcription Regulation
			Role of Histone Methylation in DNA Repair
		Acetylation
			GNAT Superfamily
			MYST Superfamily
			P300/CBP
			Nuclear Hormone–Related HATs
			HAT Complexes
			Histone Deacetylases
			Role of Histone Acetylation in Transcription Regulation
			Role of Histone Acetylation in DNA Repair
	Conclusions
	References
Chapter 4 - The Epigenetics of Noncoding RNA
	Introduction
		The Noncoding RNA
		Genetics and Epigenetics
		Epigenetic Regulation of miRNA Expression
		Epitranscriptomics of miRNAs
		Regulation of Epigenetics by miRNAs
		Plausible Interdependence Between miRNA Targeting and mRNA Methylation
		Epigenetic Regulation of lncRNAs
		Epitranscriptomics of lncRNA
		Regulation of Epigenetics by lncRNAs
	Conclusions
	Abbreviations
	Acknowledgments
	References
Chapter 5 - Prions and Prion-Like Phenomena in Epigenetic Inheritance
	Structural Heredity
		Prions of Saccharomyces cerevisiae and€Podospora anserina
		Self Driven Assembly of Hsp60 Mitochondrial Chaperonin
		Cytotaxis of Cilia and Other Complex Structures
	Mixed Heredity: A Prion That Propagates by Covalent Autoactivation
	Regulatory Inheritance
		The Lactose Operon and its Positive Feedback Loop
		Crippled Growth, a Self-Sustained and Mitotically Inheritable Signaling Pathway in the Filamentous Fungus Podospora anserina
		The White/Opaque Switch of Candida albicans, an Epigenetic Switch at the Transcription Level
	Conclusions
	References
Chapter 6 - Higher-Order Chromatin Organization in Diseases: From Chromosomal Position Effect to Phenotype Variegation
	Introduction
	CPE in Model Organisms
	Telomeric Position Effect
	Setting the Frontiers of€Chromatin Domains
	Genome Topology and Scaffolding of Chromosomal Domains
	Boundary Elements are Involved in Functional Genome Partitioning
	Chromosomal Position Effect in Human Pathologies
	Telomeric Position Effect in€Human Pathologies
	Conclusions
	References
Chapter 7 - Polycomb Mechanisms and Epigenetic Control of Gene Activity
	Introduction
	The Hardware
		PRC1
		PRC2
		Polycomb Targets
			Drosophila Polycomb Response Elements
			Mammalian PcG Recruitment
			Other Mechanisms of Recruitment
	Association of PRC2 and PRC1€Complexes
	Mechanisms of PcG Repression
	PRC2 Global Activities
	PRC2 Modulation and Product Feedback Effects
	Higher Order Interactions
	Epigenetic Maintenance or€Cellular Memory
	Maintenance of the Nonrepressed€State
	The Bivalent State
	Differentiation
	Conclusions
	Abbreviations
	References
Chapter 8 - Analysis of Gene-Specific DNA Methylation
	Introduction
	Principles of DNA Methylation Analysis
	Characteristics of Individual Techniques
		Methylation-Sensitive Restriction Enzyme–Based Analyses
		Bisulfite Sequencing
		Combined Bisulfite Restriction Analysis
		Methylation-Specific PCR
		Real-Time MSP
		MethyLight and Digital MethyLight
		Methylation-Sensitive High-Resolution Melting€Analysis
		Pyrosequencing
		MassARRAY
	Tips for Individual Methods
		Tips for Bisulfite-Mediated Conversion
		Preparation of Fully Methylated and Fully Unmethylated DNA
		Preparation of Standard DNA
		Tips for Bisulfite Sequencing
			PCR Conditions for Unbiased Amplification
			PCR Cycles to Avoid Artifacts
		Tips for MSP and Quantitative MSP
			Primer Design
			PCR Conditions for Specific Amplification
			Quantity of Template DNA
	Epilogue
	References
Chapter 9 - Methods for Assessing DNA Cytosine Modifications Genome-Wide
	Introduction
		Techniques Based on Methylation-Sensitive Restriction Endonucleases and PCR
		Targeted and Whole Genome Bisulfite Sequencing
		Infinium Methylation 450 Bead Chip
		Other Sodium Bisulfite-Based Approaches
		Methylated DNA Immunoprecipitation
		MBD Protein-Based Affinity Pulldown
		Methylated-CpG Island Recovery Assay
		5-Hydroxymethylcytosine Mapping Methodologies
		TET-Assisted Bisulfite Sequencing
		Oxidative Bisulfite Sequencing
		Future Directions and Challenges
	References
Chapter 10 - Analyses of Genome-Wide Histone Modifications in the Mammalian Genome
	Introduction
	High-Throughput Technologies to Study Histone Modifications
		ChIP-Seq in Studying Histone Modifications
			Standard ChIP-Seq
			ChIP-Seq With Spike-In Control
			ChIP-Seq With a Limited Number of Cells
			ChIP-Seq With FFPE Samples
		Analyses of Genome-Wide Histone Modification Data
	Genome-wide Profiles and Functions of Histone Modifications
		Histone Methylation
			H3K4me1/2/3
			H3K9me1/2/3
			H3K27me1/2/3
			H3K36me2/3
			H3K79me1/2/3
			H4K20me1/2/3
		Histone Acetylation
			H3K9ac and H4K20ac
			H3K27ac, H3K64ac, H3K122ac, and H4K16ac
			Other Histone Acetylations
		Histone Ubiquitination
		Histone Phosphorylation
		Histone Variants and Linker Histone H1
			H2A.Z
			MacroH2A
			H3.3
			Linker Histone H1
		Chromatin Regulators
	Histone Modifications in Key Genomic Regions
		Histone Modifications in Promoters
		Histone Modifications in Enhancers
		Histone Modifications in Gene Bodies
	Alteration of Histone Modifications in Disease
	Conclusions and Perspectives
	Acknowledgments
	Glossary
	Abbreviations
	References
Chapter 11 - Techniques for Genome-Wide Expression Analysis of Noncoding RNA
	Introduction
	Mining RNA-SEQ Data for ncRNAs
		Algorithm for Long ncRNA Detection
		Algorithm for Small ncRNA Detection
		Algorithm for circRNA Detection
	cDNA Library Construction
		Ribosomal RNA Depletion of cDNA Libraries
		Library Preparation for Strand-Specific RNA-seq
		Detection of Low-Abundance RNA Species
	Estimating the Transcription and Degradation Rates of Transcripts
		A Genome-Wide Approach to Determine RNA Stability
		Detecting Unstable ncRNAs by Inhibiting the Decay Process of the ncRNAs
		Estimation of the Transcription Rate through Detection of Nascent Transcripts
		Kinetic Determination of RNA Production and Degradation
	Conclusions
	Glossary
	References
Chapter 12 - Computational Epigenetics
	Introduction
	Approaches to Measure DNA Methylation and Histone Modifications
	Public Resources for Epigenetic Data
		Bisulfite Sequencing
	Processing Microarray-Based DNA Methylation Data
		Methylated DNA Enrichment
		ChIP-Chip and ChIP Sequencing
	Differentially Methylated Regions
	Prediction of Epigenetic Status
	Integrative Epigenomics
	Concluding Remarks
	Acknowledgments
	References
Chapter 13 - Epigenetic Modifications in Eukaryotes and Prokaryotes are Equally Intriguing
	Introduction
	Biological Significance of Acetylation in Eukaryotic Organisms
	Acetylation of NonHistone Proteins in Regulating Cellular Functions
	Role of Acetylation in Lower Organisms
	Role of Lysine Methylation in Higher Eukaryotes
	Role of Methylation in Lower Organisms
	Role of Deacetylation and Demethylation in Gene Regulation
	Role of Phosphorylation in Higher Eukaryotes
	Role of Phosphorylation in Lower Organisms
	Cross-Talks Between Epigenetic Modifications
	Conclusions and Future Perspectives
	Acknowledgments
	References
Chapter 14 - Drosophila Epigenetics
	Introduction: Drosophila as a Model Organism in Epigenetic Research
	Epigenetic Modification of Histone Proteins Regulate Chromatin Packaging and Gene Control in Drosophila
		Histone Acetylation
		Histone Methylation
	Position Effect Variegation
		Heterochromatin Within the Drosophila Genome
		Protein Regulators of Position Effect Variegation
		Epigenetic Histone Modifications Regulate PEV in Drosophila
	The Role of Epigenetics During Drosophila Development: Epigenetic Memory
		Epigenetic Modifications Maintain Patterns of HOX Gene Expression Throughout Drosophila Development
		Mechanisms of Silencing and Activation
		PcG Proteins and Gene Repression
		TrxG Proteins and Gene Activation
		PREs and PcG-TrxG–Mediated Gene Expression
		Transgenerational Epigenetic Inheritance: “Epigenetic Memory”
		Epigenetics During S Phase
		Epigenetics During M Phase
	Dosage Compensation
		The MSL Complex/DCC
		Regulation of DCC Targeting to the X Chromosome
		DCC Spreading and Target Recognition
		Transcriptional Activation of Active X-Linked Genes by the DCC
	The Epigenetic Language in Postmitotic Neurons Underlying Cognitive Function
		Activity-Dependent Histone Acetylation and Cognitive Function
		HAT: HDAC Interplay in Cognitive Function
		Deregulation of HAT Activity in the Etiology of Alzheimer’s Disease
		Environmental Enrichment Improves Learning and Memory in Drosophila
	Conclusions
	Glossary
	Abbreviations
	References
Chapter 15 - Mouse Models of Epigenetic Inheritance: Classification, Mechanisms, and Experimental Strategies
	Two Types of Epigenetic Inheritance (EI): Mitotic Versus Generational
	EI Signals: Cis Versus Trans
	Mice as Model Mammals
	Mouse EI Models: A Brief History
	Conventional Mouse EI Models
		Spontaneous Random Epigenetic Variations
			Mitotic EI Models
				Variegated expression: differential gene expression in the cells of the same type within a mouse
				Intangible variance: phenotypic variation in isogenic littermates raised under the same condition
				Relationship between variegated expression and variable expressivity
				Biological significance of phenotypic noise
			Generational EI Models
		Experimentally Induced EI
			Induction of Epigenetic Lesion: Soma Versus Germ
			Propagation of Epigenetic Lesion Across Generations: Mode of Inheritance and Determinant of Durability
	Targeting Epigenetic Modifications to Reporter Genes: A Unique EI Model Tractable for Mechanistic Studies
	Conclusions
	Glossary
	References
Chapter 16 - Plant Epigenomics
	Introduction
	DNA Methylation
		Functions and Mechanisms of DNA Methylation
		Interactions With Other Epigenetic Factors
		Methods To Interrogate DNA Methylation
		Stability, Heritability, and Agricultural Significance
	Histone Modifications in Plants
		Linker Histones in Plants
		Types of Histone Modifications
		Mechanism of Action of Histone Modifying Enzymes
		Role of Histone Modifying Enzymes in Developmental Processes
		Regulation of Gene Expression by Histone Modifying Enzymes During Biotic and Abiotic Stress
		Crosstalk of Histone Modification and DNA Methylation
	Role of Epigenetic Marks in Plant Development
	Histone Modifications and Gene Expression in Response to Abiotic and Biotic Stress
	Epigenome Editing—A New Approach for Crop Improvement
		Tools for Epigenome Editing
		Epigenome Editing Using Genome Editing Tools
	Future Perspectives
	Glossary
	References
Chapter 17 - Dynamic Changes in DNA Modifications During Key Embryonic Transitions
	Introduction
	Embryo Development
	Epigenetic Transitions in the Early Embryo
	Setting the Embryonic Epigenetic Ground State
	Changes Accompanying Differentiation
	The Roles for the Global Demethylation of Pluripotent Cells
	Roles of TET-Mediated Modifications of 5meC
	Stress During Key Embryonic Transitions Have Lifelong Consequences
	Conclusions
	References
Chapter 18 - Epigenetic Biomarkers
	Introduction
	Epigenetic Biomarkers Offer Distinct Advantages Over Genetic€Biomarkers
	Minimally Invasive Tissues are Suitable for Detecting Epigenetic€Biomarkers
	Field Cancerization and Epigenetic Biomarkers
	Potential Methylation Biomarkers in Cancer and Other€Disease
	Potential Histone Modification Biomarkers in Cancer and Other€Diseases
	Potential Noncoding RNA Biomarkers in Diseases
		Potential miRNA Biomarkers in Cancer and Other Diseases
		Potential Long Noncoding RNA Biomarkers in Cancer and Other Diseases
	Epigenetic Biomarker Detection Methods in Clinical Application
	Challenges and Future Perspectives
	Abbreviations
	References
Chapter 19 - Metabolic Regulation of DNA Methylation in Mammalian Cells
	DNA Methylation as a Dynamic Epigenetic Process Requiring Constant Methyl Donors
	Mechanisms of DNA Demethylation
	One-Carbon Metabolism as the Source of Methyl Donors for DNA Methylation
	S-Adenosylmethionine: Master of the Methylome
	Regulators of SAM
		Biochemical Inhibitors
		Genetic Variation and SAM
	Methyl Donor/Cofactor Availability and DNA Methylation
	Disruption of One-Carbon Metabolism, DNA Methylation, and Disease: What is the Link?
	Concluding Remarks
	References
Chapter 20 - Dietary and Metabolic Compounds Affecting Covalent Histone Modifications
	Introduction
	Histone Acetylation
		Histone Deacetylases
		Histone Acetyltransferases
	Histone Methylation
	Other Histone Modifications
	Conclusions
	Glossary
	Acknowledgments
	References
Chapter 21 - Epigenetics, Stem Cells, Cellular Differentiation, and Associated Hereditary Neurological Disorders
	Introduction to Epigenetics
	Epigenetics and the Human Brain
		Stem Cells
		Eukaryotic Chromosomal Organization
		Histones and Their Structure
		Epigenetics and Neurological Disorders
			Huntington’s Disease and Mesenchymal Stem Cells
			Parkinson’s Disease and Neural Stem Cells
			Rett Syndrome and Induced Pluripotent Stem Cells
			The Spinocerebellar Ataxia and Mesenchymal Stem Cells
				SCA1 (OMIM #164400);
				SCA 7 (OMIM # 164500);
				SCA 8 (OMIM # 608768);
			Multiple Sclerosis and Hematopoietic Stem Cells
	Conclusions
	Abbreviations
	References
	Further Reading
Chapter 22 - Epigenetic Regulation of Neuron’s Regenerative Abilities After Spinal Cord Injury
	Introduction
	DNA Methylation in Axon Growth and Regeneration
	Histone Posttranslational Modifications in Axon Growth and Regeneration
	Advantages of Studying Axonal Regeneration in Larval Lamprey€CNS
	Changes in HATs and HDACs mRNA Expression in Lamprey CNS After Spinal Cord Transection
	Chromatin-Independent Effects of Protein Acetylation on Axon Growth and Regeneration
	The Role of Long Noncoding RNAs (lncRNAs) in Nerve Regeneration
	Conclusions
	Acknowledgments
	Abbreviations
	References
Chapter 23 - Epigenetics of Memory Processes
	Introduction
	Epigenetic Modification of Histones Underlying Memory
	Covalent Modification of DNA Underlying Memory
	Summary
	Acknowledgments
	Abbreviations
	References
Chapter 24 - Transgenerational Epigenetics
	Introduction
	Epigenetic Consequences of Prenatal Maternal Exposures
	Postnatal Maternal Regulation of the Epigenome
	Paternal Influence on Offspring Development
	Transgenerational Effects of Parental Influence
	Germline-Mediated Transgenerational Inheritance
	Experience-Dependent Transgenerational Inheritance
	Epigenetics, Plasticity, and Evolving Concepts of Inheritance
	Acknowledgments
	References
Chapter 25 - Aging Epigenetics
	Introduction
	DNA Methylation Changes During Aging
	Dynamics of DNA Methylation During Aging
	Global Methylation Changes in Aging Cells
	Gene-Specific Methylation Changes
	One Carbon Metabolism in Aging
	Changes of Higher Order Chromatin Structure in Aging
	Histone Modifications During Aging
	HAT:HDAC Balance
	Sirtuins
	Epigenetic Control of Telomeres in Aging
	Other Epigenetic Mediators That Influence Longevity
	Model of Age-Dependent Epigenetic Drift
	Lessons From Twin Research
	Conclusions and Future Directions
	References
Chapter 26 - Evolution of Epigenetic Mechanisms in Plants: Insights From H3K4 and H3K27 Methyltransferases
	Introduction
	Histone Lysine Methylation
	HKMTs in Plants
	Evolution of Plant HKMTs Methylating H3K4
	Evolution of Plant HKMTs Methylating H3K27
	Perspectives
	Acknowledgments
	References
Chapter 27 - Evolution of Epigenetic Mechanisms in Animals and Their Role in Speciation
	Introduction
	Diversification of DNA Methylation in Animals
		Global DNA Methylation Levels
		DNA Methylation Toolkit
		Genome-Wide Methylomes
	Epigenetic Mechanisms as Consolidators of Speciation
		Polyploid Speciation and Reproductive Isolation
		Chromatin Remodeling after Speciation
	Epigenetic Mechanisms as Driving Force of Evolution
		The Role of Epigenotypes in Environmental Adaptation
		The Role of Epigenotypes in Evolution
		The Marbled Crayfish Project on Environmental and Evolutionary Epigenetics
	Conclusions and Perspective
	Acknowledgments
	References
Chapter 28 - Adaptive Evolution and Epigenetics
	Introduction
	Epigenetic Variation
	Induced Epigenetic Changes
	Spontaneous Epigenetic Variation
	Modeling Evolution
	Supply of Epigenetic Mutations
	Stability of Epigenetic Mutations
	Distribution of Mutational Effects
	Model for Adaptive Evolution With Epigenetic Variation
	Limits of Epigenetic Contributions to Adaptation
	Future Directions
	Acknowledgments
	References
Chapter 29 - Epigenetics of Livestock Breeding
	Introduction
	Development of Animal Breeding
	Epigenetic Source of Phenotypic Variation in Livestock Traits
		Nutritional Epigenomics and Other Environmental Influences on Epigenetic Marks
		MicroRNAs as Potential Noninvasive Biomarkers of Fertility
		Evidence of the Effects of Epigenetic Marks on Health Outcomes
		Epigenetic Marks Regulate Lipid Metabolism and Milk Traits
	Revisiting Animal Breeding Planning
		Transgenerational Epigenetic Inheritance
		Genomic Imprinting
		The Role of Epigenetic Marks in Livestock Breeding
		Application of Genome Editing Technology in Livestock Epigenetics and Breeding
	Conclusions
	Acknowledgment
	Glossary
	References
Chapter 30 - Nutritional Epigenome and Metabolic Syndrome
	Introduction
	Epigenetic Mechanism and Metabolic Syndrome
	Impact of Parental Nutrition on Fetal Reprogramming
	Dietary Factors and Metabolic Epigenome
		Nutritional Condition
		Protein
		Methyl Donors
		Polyphenols
		Polyunsaturated Fatty Acid
	Conclusions and Perspectives
	Acknowledgments
	Abbreviations
	References
Chapter 31 - Environmental Influence of Epigenetics
	Introduction
	The Extent of Environmental Influence
		Parental and Ancestral Predisposition
		Prenatal Exposure
		Postnatal and Life Time Influence
	Exerting Environment
	Mental or Physiological Environment
		Enriched Environment
		Activity and Experience-Dependent Changes
			Activity Related Neuronal Plasticity Through Epigenetics
			Experience And Memory Formation Through Epigenetics
		Stress
			Prenatal Stress
			Childhood Adversity or Early Life Stress
		Exercise
		Nutrition
	Hazardous Environmental Pollutants and Chemicals
		Heavy Metals and Pollutants
			Lead
			Arsenic and Cadmium
			Methylmercury
			Bisphenol A
			Pesticides
		Prescription Medicine
			Valproic Acid
			γ-Hydroxybutyrate (GHB)
		Addictive Substances
			Alcohol
			Cocaine
			Cannabinoids
			Opioids
			Nicotine
	Conclusions and Future Direction
	Acknowledgments
	Abbreviations
	References
Chapter 32 - The Gut Microbiota Influence on Human Epigenetics, Health, and Disease
	Introduction
	Early Microbiome Exposure and Epigenetic Influence
	The Human Gut Microflora
	The Microbiome, Epigenetics, and Effect on Metabolism
	Gut Microbiota, Inflammation, and Colorectal Carcinogenesis
	Pathogenic Infections and Cancer
	Pathogenic Infections and Epigenetic Modifications
		Bacterial Infections
			Helicobacter pylori Infection and the Stomach
		Viral Infections
	Viruses and Epigenetic Role in Cancer Development
	Bacterial Influence on the Cell Cycle
	Conclusive Remarks
	Abbreviations
	References
Chapter 33 - Population Pharmacoepigenomics
	Introduction
	General Aspects of Population Pharmacoepigenomics
	Population Variations of Epigenetic Patterns and Population Pharmacoepigenomics
	Human Epigenome Projects and Population Pharmacoepigenomics
	Population Pharmacoepigenomics in Relation to Pharmacokinetics
	Population Pharmacoepigenomics in Relation to Pharmacodynamics
	The 3D and 4D Chromatin Structures in the Nuclei of Cells in the Liver and Other Body Organs and Population Pharmacoepigenomics
	Population Pharmacoepigenomics in Relation to Adverse Drug Reactions and Drug Interactions
	Conclusions
	Glossary
	Abbreviations
	References
Chapter 34 - Cancer Epigenetics
	Introduction
	Epigenetic Influences Over a Life Time and Cancer Risk
	Mechanisms of Epigenetics in Cancer: Writers, Readers, and Erasers
		DNA Methylation
		Histone Modification
		Noncoding RNA
		Importance of Epigenetic Changes Together with Genetic Alterations
		Epigenetics in Intratumoral Heterogeneity and Therapeutic Resistance
	Genetic and Epigenetic Classification of Cancer
		Limitations to Epigenetic Classification and Prognostication
	Epigenetic Biomarkers in Cancer
		Cancer Epigenome in Epidemiology
	Epigenetics as Cancer Therapeutic Targets
	Future Perspectives
	Abbreviations
	References
Chapter 35 - The Role of Epigenetics in Autoimmune Disorders
	The Immune System and Autoimmunity
	Epigenetics of Immune Cells
		T Cells
		B Cells
		Macrophages
		Dendritic Cells
	Epigenetics of Systemic Lupus Erythematosus
	Epigenetics of Rheumatoid Arthritis
	Multiple Sclerosis
	Type 1 Diabetes Mellitus
	Systemic Sclerosis
	Use of Epigenetic Modifiers for Potential Diagnosis and Therapy in Autoimmune Diseases
	Concluding Remarks
	Abbreviations
	References
Chapter 36 - Epigenetics of Brain Disorders
	Introduction
	Epigenetic Mechanisms Important for the Brain
		DNA Methylation
		Histone Modifications
		MicroRNAs
	Epigenetic Dysregulation in Neurodevelopmental Disorders: The Example of Rett Syndrome
	Epigenetic Dysregulation in Neurodegenerative Disorders: The Example of Alzheimer’s Disease
	Epigenetic Dysregulation in Psychiatric Disorders: The Example of Depression
	Epigenetic Dysregulation by Environmental Stress: The Example of Early Life Stress
	Conclusions and Outlook
	Acknowledgments
	References
Chapter 37 - Epigenetics of Metabolic Diseases
	Introduction
	Lifestyle Factors and Age Affect the Epigenome
		Age and the Epigenome
		Diet, Metabolism, and the Epigenome
		Physical Activity, Inactivity, and the Epigenome
	Epigenetic Memory, Prenatal Exposure, and Risk of Metabolic Disease
		Thrifty Phenotype and Birth Weight
		Diabetes in Pregnancy
	Epigenetic Features of Metabolic Diseases
		Metabolic Syndrome
		Obesity
		Type 2 Diabetes
	Conclusions
	Abbreviations
	References
Chapter 38 - Imprinting Disorders in Humans
	Introduction
	Types of (Epi)Mutations in IDs
		Epimutations
		Uniparental Disomy
		Chromosomal Deletions and Duplications
		Genomic Point Mutations in ID Patients
	The Chromosomal Region 11p15
	General Observations in IDs
	Transient Neonatal Diabetes Mellitus: Chromosome 6
	Silver–Russell Syndrome: Chromosomes 7 and 11
	Beckwith–Wiedemann Syndrome: Chromosome 11
	Temple Syndrome and Kagami–Ogata Syndrome: Chromosome 14
	Angelman and Prader–Willi Syndromes: Chromosome 15
	Chromosome 20 and the GNAS Locus
	The New “Monogenetic” IDs
	Multilocus Imprinting Disturbances in IDs
	Genetic Testing for IDs
	Concluding Remarks
	References
	Further Reading
Chapter 39 - DNA Demethylation Agents in Clinical Medicine
	Introduction
	The Rationale for Using DNA Methylation Inhibitors in Treating Cancer: Hypermethylation of Tumor Suppressor Genes and Dereg...
	Preclinical Evidence for Pharmacological DNA Demethylation as an Anticancer Strategy
	The Role of DNMT3A and DNMT3B in Cancer
	Clinical Studies With DNA Methylation Inhibitors
	Combination of AZA or DAC With Other New or Classical Chemotherapy Drugs
	The Role of Demethylation in Cancer: Potential Risk of Promoting Cancer and Metastasis by Demethylating Agents
	Challenges and Questions
	DNMT Inhibitors as Potential Treatment of Mental Health Conditions
	Challenges and Prospective
	Acknowledgments
	References
	Further Reading
Chapter 40 - Clinical Applications of Histone Deacetylase Inhibitors
	Introduction
	Histone Deacetylase Inhibitors for the Treatment of Hematological Malignancies
		Vorinostat (Zolinza, Suberoylanilide Hydroxamic Acid)
		Panobinostat (Farydak, LBH589)
		Romidepsin (Istodax, Depsipeptide, FK228)
		Entinostat (MS-275, SND-275)
		Valproic Acid
		Belinostat (Beleodaq, PXD101)
	Histone Deacetylase Inhibitors in the Treatment of Solid Tumors
		Vorinostat (Zolinza, Suberoylanilide Hydroxamic Acid)
		Panobinostat (Farydak, LBH589)
		Romidepsin (Istodax, Depsipeptide, FK228)
		Entinostat (MS-275, SND-275)
		Valproic Acid
		Belinostat (Beleodaq, PXD101)
	Clinical Applications of Histone Deacetylase Inhibitors for Noncancer Diseases
		Current Therapeutic Applications
			Valproic Acid
			Phenylbutyrate
		Clinical Evaluation of Valproic Acid and Phenylbutyrate
		HDAC Inhibitor Dependent Reactivation of Latent HIV
	Conclusions and the Future Directions of the Clinical Applications of HDAC Inhibitors
	References
Chapter 41 - Combination Epigenetic Therapy
	Introduction
	Chromatin-Remodeling Agents, Combined Treatment, and Targeted Therapy
		DNA Methylation/Demethylation and Combined Treatment
			DNMT inhibitors
		Histone Modifications and Histone-Modifying Enzymes for Epigenetic Treatment
			HMT
				HMT inhibitors
			Histone Acetylation/Deacetylation and Epigenetic Modifiers
				HAT and HDAC
				HDAC inhibitors
	Conclusions and Future Perspectives
	References
Chapter 42 - New Directions for Epigenetics: Application of Engineered DNA-Binding Molecules to Locus-Specific Epigenetic Research
	Introduction
	General Information on Engineered DNA-Binding Molecules
		ZF Proteins
		TAL Proteins
		CRISPR/Cas
	Locus-Specific Epigenome Editing
		Proof-of-Concept Research on Locus-Specific Epigenome Editing
			DNA Methylation
			DNA Demethylation
			Histone Modification
		Locus-Specific Epigenome Editing Aimed at Obtaining Mechanical Insight into Disorders and Therapeutic Applications
		Potential Problems with Locus-Specific Epigenome Editing
		Advanced Epigenome Editing Tools
		Characteristics of Engineered DNA-Binding Molecules
	Locus-Specific Identification of Epigenetic Molecules that Interact with Target Genomic Regions
		Development of Locus-Specific ChIP: iChIP and enChIP
		Identification of Epigenetic and Related Molecules in a Locus-Specific Manner by enChIP
		In Vitro enChIP
	Conclusions
	References