Introduction to Epigenetics

Preface
Acknowledgments
Contents
1: Biology of Chromatin
	1.1	 Introduction: Epigenetic Regulation in the Context of the Genome
		1.1.1	 Background: Gene Expression and Chromatin
		1.1.2	 Discovery of the Nucleosomal Structure of the Genome
	1.2	 The Structure of the Nucleosome
		1.2.1	 Histone Variants
	1.3	 Histone Modifications
		1.3.1	 Nomenclature for Histone Modifications
		1.3.2	 Combinatorial Modifications at Pericentric Heterochromatin
		1.3.3	 Histone Modifications at High Resolution
		1.3.4	 Chromatin Modifications Associated with Transcription Units
		1.3.5	 A Concept of Writers, Readers, and Erasers of Histone Modifications
	Method Box 1.1: Chromatin Immunoprecipitation
	1.4	 DNA Modifications
		1.4.1	 DNA Cytosine Methylation
		1.4.2	 DNA Cytosine Hydroxymethylation
		1.4.3	 Interaction of DNA and Histone Modifications
	Method Box 1.2: Analysis of DNA Modifications
	1.5	 Chromatin Organization and Compartmentalization in the Cell Nucleus
		1.5.1	 Replication of Pericentric Heterochromatin Domains
		1.5.2	 Topologically Associating Domains
		1.5.3	 Structural Maintenance of Chromosomes Complexes
	Method Box 1.3: Chromatin Conformation Capture (. Box Fig. 1.3)
	References
2: Chromatin Dynamics
	2.1	 Basic Nuclear Activities
	2.2	 Connecting Nucleosomes to DNA Sequence
	2.3	 Nucleosome Remodeling
		2.3.1	 A Template for Transcription
		2.3.2	 Chromatin Remodeling Complexes
	Methods Box 2.1: Determining DNA Accessibility in a Chromatin Template
	2.4	 Nucleosome Assembly
		2.4.1	 Histone Variants and Histone Chaperones
		2.4.2	 The Replication Fork: Still the Major Enigma in Epigenetics
	References
3: Cellular Memory
	3.1	 Maintaining Cellular Fates
	3.2	 PcG/TrxG System Maintaining Cellular Memory
	3.3	 Biochemical Characterization and Molecular Function of PcG/TrxG Proteins
	3.4	 Targeting and Propagation of PcG/TrxG-Controlled Chromatin Domains
	3.5	 Switching Memory and the Role of Non-coding RNAs
	3.6	 Losing Memory
	References
4: Dosage Compensation Systems
	4.1	 Introduction: Evolution of Chromosome-Wide Dosage Compensation
		4.1.1	 Consequences of Gene Dosage Differences Arising from Sex Chromosome Erosion
	4.2	 The Dosage Compensation Complex of the Fruit Fly Drosophila melanogaster
	4.3	 X Chromosome Inactivation in Mammals
		4.3.1	 The Mammalian Dosage Compensation Mechanism
		4.3.2	 Regulation of XCI in Different Mammals
	4.4	 X Chromosome Dosage Compensation in Caenorhabditis elegans
	References
5: Genomic Imprinting
	5.1	 Discovery of the Non-equivalence of Maternal and Paternal Genomes
		5.1.1	 Genome-Wide Imprinting in Insects
		5.1.2	 Discovery of Genomic Imprinting at an Individual Locus in Maize
		5.1.3	 Demonstrating the Non-equivalence of Parental Genomes in Mammals
	5.2	 Characteristics of Imprinted Genes in Mammals
		5.2.1	 Molecular Characteristics of Imprinted Gene Clusters
		5.2.2	 Molecular Mechanisms Leading to Imprinted Expression
		5.2.3	 The Life Cycle of a Genomic Imprint
	5.3	 Genomic Imprinting and Human Disease
	5.4	 Genomic Imprinting in Flowering Plants
		5.4.1	 Genomic Imprinting Occurs Predominantly in the Endosperm But Also Exists in the Embryo
		5.4.2	 Mechanisms Underlying Imprinting Show Similarities Between Mammals and Plants
	5.5	 Evolution of Genomic Imprinting
	References
6: RNA-Based Mechanisms of Gene Silencing
	6.1	 The Unusual Behavior of Transgenes Led to the Discovery of Novel RNA-Based Silencing Mechanisms
		6.1.1	 Conserved Components of RNA-Based Silencing Mechanisms
	6.2	 Post-Transcriptional Gene Silencing (PTGS)
		6.2.1	 The Biogenesis and Function of microRNAs
		6.2.2	 Genome Defense by siRNA-Mediated Silencing
	6.3	 Transcriptional Gene Silencing (TGS)
	6.4	 Paramutation
		6.4.1	 The cis-Regulatory Elements Controlling Paramutation and trans-Acting Factors Link Paramutation to RdDM
	References
7: Regeneration and Reprogramming
	7.1	 Types of Regenerative Phenomena
		7.1.1	 Regenerating from a Blastema
		7.1.2	 Changing Potency by Transdifferentiation
		7.1.3	 Signaling in the Blastema
	7.2	 Stem Cells in the Adult
	7.3	 Sources of Pluripotent Stem Cells
	7.4	 Chromatin Dynamics During Reprogramming
	7.5	 Regenerative Therapies
	References
8: Epigenetics and Cancer
	8.1	 Epigenetics and Cancer
	8.2	 DNA Methylation and Cancer
		8.2.1	 DNA Hypermethylation in Cancer
		8.2.2	 DNA Hypomethylation in Cancer
		8.2.3	 Loss of Imprinting Through Alterations of DNA Methylation
		8.2.4	 Mutations in the DNA Methylation Machinery in Cancers
			8.2.4.1	 Mutations of de novo DNA Methyltransferase 3a
			8.2.4.2	 Mutations of Ten-Eleven Translocation 2 (TET2)
		8.2.5	 Epigenetic Inhibitors of DNA Methyltransferases in Cancer Therapy
	8.3	 Polycomb Group Proteins and Cancer
		8.3.1	 Alterations of PcG Activity in Cancer
		8.3.2	 Mutations of Affecting Lysine 27 of Histone H3 Occur in Multiple Cancers
		8.3.3	 EZH2 Inhibitors in Cancer Therapy
	8.4	 Histone Acetylation and Deacetylation in Cancers
		8.4.1	 Alterations of Histone Acetyltransferases in Cancer
		8.4.2	 Acetyl-Lysine Recognition Proteins and Cancer
		8.4.3	 Alterations of Histone Deacetylases in Cancer
		8.4.4	 HAT and HDAC Inhibitors in Cancer Therapy
	8.5	 Chromatin Remodeling Factors and Cancer
		8.5.1	 SWI/SNF Complexes and Cancer
		8.5.2	 ISWI Complexes and Cancer
		8.5.3	 The NuRD Complex and Cancer
		8.5.4	 The INO80 Complex and Cancer
	References
9: Epigenetics and Metabolism
	9.1	 Epigenetics and Metabolism
	9.2	 Acetyl-Coenzyme A (Acetyl-CoA)
		9.2.1	 Biosynthesis of Acetyl-CoA
		9.2.2	 Acetyl-CoA as Cofactor of Histone Acetyltransferases
	9.3	 Nicotinamide Adenine Dinucleotide (NAD)
		9.3.1	 Biosynthesis of NAD
		9.3.2	 NAD as Cofactor of Sirtuins and PARPs
			9.3.2.1	 Sirtuins
			9.3.2.2	 PARPs
	9.4	 S-adenosylmethionine (SAM)
		9.4.1	 Biosynthesis of SAM
		9.4.2	 SAM as Cofactor of DNA and Histone Methyltransferases
	9.5	 Flavin Adenine Dinucleotide (FAD)
		9.5.1	 Biosynthesis of FAD
		9.5.2	 FAD as Cofactor of Lysine Demethylase 1 (LSD1)
	9.6	 α-Ketoglutarate (αKG)
		9.6.1	 Biosynthesis of α-Ketoglutarate
		9.6.2	 αKG as Cofactor of TET-Family DNA Demethylases and Jumonji C-Family Histone Demethylases
	References
Glossary
Index