DNA Methyltransferases - Role and Function

Preface
Contents
About the Editors
1: Mechanisms and Biological Roles of DNA Methyltransferases and DNA Methylation: From Past Achievements to Future Challenges
1.1 Discovery of DNA Methylation
1.2 Discovery and Early Work on DNA MTases
1.3 DNA MTases Contain Conserved Amino Acids Sequence Motifs
1.4 Structure and Mechanism of DNA MTases
1.5 Molecular Evolution of MTases
1.6 Early Views on the Biological Role of DNA Methylation
1.7 Genetic Studies on DNMTs in Mammals
1.8 Structure, Function, and Regulation of Mammalian DNA MTases
1.9 Discovery of TET Enzymes
1.10 Methods for Site-Specific Detection of DNA Methylation
1.11 DNA MTases and Bacterial Epigenetics
1.12 Role of DNA Methylation in Cancer
1.13 Application of MTases in Artificial Epigenetic Systems
1.14 Conclusions and Outlook
References
2: DNA Methylation in Prokaryotes
2.1 Introduction
2.2 CcrM Methylation
2.3 Dam Methylation
2.3.1 Role of Dam Methylation in DNA Mismatch Repair
2.3.2 Control of Chromosome Replication by Dam Methylation
2.3.3 Transcriptional Control by Dam Methylation
2.3.3.1 Temporal Regulation of Gene Expression by Dam Methylation
2.3.3.2 Regulation of Bistability by Dam Methylation
2.4 Phase Variable DNA Adenine Methylation
2.5 Additional Examples of DNA Adenine Methylation
2.6 C5-Methylcytosine
2.7 N4-Methylcytosine
2.8 Biomedical and Biotechnological Applications of Dam Methylation
References
3: Domain Structure of the Dnmt1, Dnmt3a, and Dnmt3b DNA Methyltransferases
3.1 DNA Methylation and Methyltransferases in Mammals
3.2 Enzymes Responsible for the Establishment of DNA Methylation Patterns
3.2.1 PWWP Domain
3.2.2 ADD Domain
3.2.3 Catalytic Domain
3.2.4 Functions of Other Regions
3.2.5 Factors That Guide Dnmt3 to the Regions to Be Methylated
3.2.6 Correlation Between de novo DNA Methylation and Histone Modifications
3.3 Enzymes Responsible for the Maintenance of DNA Methylation Patterns
3.3.1 NTD
3.3.2 RFTS Domain
3.3.3 CXXC
3.3.4 Two BAH Domains
3.3.5 Catalytic Domain
3.4 Cross-Talk Between De Novo-Type and Maintenance-Type DNA Methyltransferases
3.5 Conclusions and Perspective
References
4: Enzymology of Mammalian DNA Methyltransferases
4.1 Introduction
4.2 General Features of Mammalian DNMTs
4.2.1 Structure and Domain Composition of Mammalian DNMTs
4.2.2 Catalytic Mechanism of C5-MTases
4.2.3 Regulation and Targeting of DNMTs
4.3 Structure, Function, and Mechanism of DNMT1
4.3.1 Domain Composition of DNMT1
4.3.2 Structures of DNMT1 and Allosteric Regulation
4.3.3 Specificity of DNMT1
4.3.4 Processivity of DNMT1
4.3.5 Allosteric Regulation and Targeting of DNMT1
4.3.5.1 The DNMT1-PCNA Interaction
4.3.5.2 The DNMT1-UHRF1 Interaction
4.3.5.3 Binding of the DNMT1-RFTD to Ubiquitinated H3 Tails
4.3.5.4 Binding of DNMT1 to Heterochromatic Chromatin Marks
4.3.5.5 Regulation of Activity and Specificity of DNMT1 by Nucleic Acid Binding
4.3.6 PTMs of DNMT1
4.3.6.1 Phosphorylation of DNMT1
4.3.6.2 Acetylation and Ubiquitination of DNMT1
4.3.6.3 Lysine Methylation of DNMT1
4.4 Structure, Function, and Mechanism of DNMT3 Enzymes
4.4.1 Domain Composition of DNMT3 Proteins
4.4.2 Structures of DNMT3A and DNMT3B
4.4.3 Allosteric Regulation of DNMT3A
4.4.4 Specificity of DNMT3 Enzymes
4.4.5 Kinetic Mechanism of DNMT3 Enzymes
4.4.6 Oligomerization of DNMT3 Enzymes
4.4.6.1 Protein Multimerization of DNMT3 Enzymes
4.4.6.2 Multimerization of DNMT3A and DNMT3A/DNMT3L on DNA
4.4.7 Direct Chromatin Interaction of DNMT3 Enzymes
4.4.7.1 Binding of the DNMT3 ADD Domain to H3 Tails
4.4.7.2 Binding of DNMT3 PWWP Domain to H3 Methylated at K36
4.4.7.3 H2AK119ub Binding of DNMT3A1
4.4.8 Interaction Partners of DNMT3s
4.4.8.1 DNMT3A/DNMT3L Interaction
4.4.8.2 Interaction of DNMT3A with MeCP2
4.4.8.3 Other DNMT3A Interacting Proteins
4.4.9 Phosphorylation of DNMT3A
4.4.10 Binding of Regulatory DNA and RNA to DNMT3 Enzymes
4.5 Outlook
References
5: Genetic Studies on Mammalian DNA Methyltransferases
5.1 Distinct Roles of Dnmt1 and Dnmt3 Families in DNA Methylation
5.1.1 Dnmt1: The Maintenance DNA Methyltransferase
5.1.2 Dnmt3 Family: Key Components of De Novo Methylation Machinery
5.1.3 Uhrf1: A Major Regulator of Maintenance DNA Methylation
5.2 Dnmts in Embryonic Development and Cellular Differentiation
5.2.1 Roles of Dnmts in Embryonic Development
5.2.2 Roles of Dnmts in Cellular Differentiation and Maintenance of Cell Identity.
5.2.3 DNMT Mutations in Human Diseases
5.3 Dnmts in Genomic Imprinting
5.3.1 Establishment of DNA Methylation Imprints during Gametogenesis
5.3.2 Maintenance of DNA Methylation Imprints during Development
5.3.3 Erasure of DNA Methylation Imprints in Primordial Germ Cells
5.3.4 Noncanonical Genomic Imprinting
5.4 Concluding Remarks
References
6: Structure and Mechanism of Plant DNA Methyltransferases
6.1 Introduction
6.2 Structure and Mechanism of Plant DNA MTases
6.2.1 Structural Mechanism of the Maintenance of CHG Methylation in Plants
6.2.1.1 Overview of Plant CHG DNA Methylation
6.2.1.2 Structure and Mechanism of CMT3
6.2.1.3 Structure and Mechanism of KRYPTONITE
6.2.2 Mechanism of CMT2-Mediated CHH Methylation
6.2.3 RNA-Directed DNA Methylation (RdDM)
6.2.3.1 Overview of RdDM
6.2.3.2 Structure and Mechanism of DRM2
6.2.4 Potential Mechanism of MET1 in CG Methylation Maintenance
6.3 Conclusion and Perspective
References
7: DNA Methylation in Honey Bees and the Unresolved Questions in Insect Methylomics
7.1 Introduction
7.2 Genotype to Phenotype
7.3 The Epigenetic Control of Gene Expression
7.4 DNA Methylation
7.4.1 Conserved and Non-Conserved Features of DNA Methylation Enzymology in Animals
7.4.2 DNMTs and Establishing DNA Methylation Patterns in the Honey Bee
7.4.3 How do TET Enzymes Contribute to Gene Regulation in the Honey Bees and Other Insects?
7.4.4 DNA Methylation Patterns Across Invertebrates
7.4.5 Does Gene Body Methylation Direct Gene Expression in Insects?
7.5 Conclusion
References
8: N6-methyladenine: A Rare and Dynamic DNA Mark
8.1 Introduction
8.2 Types of DNA Modifications
8.3 Discovery of 6mA in Various Eukaryotes
8.4 Abundance of 6mA
8.5 Methods of Detecting 6mA
8.6 6mA Regulating Enzymes
8.6.1 DNA Methyltransferases
8.6.2 Mechanism of 6mA Methyltransferases
8.7 DNA Adenine Demethylation
8.8 6mA Binding Proteins
8.9 Biological Functions of 6mA
8.9.1 Effects of Adenine Methylation on DNA Structure
8.9.2 Restriction-Modification Systems
8.9.3 DNA Damage Control
8.9.4 Effect on Transcription
8.9.5 Nucleosome Positioning
8.9.6 Cell Cycle Regulation
8.9.7 Transgenerational Inheritance
8.10 Conclusions and Future Directions
References
9: Pathways of DNA Demethylation
9.1 DNA Methylation: One Building Block of the Epigenome
9.2 DNA Methylation Reprogramming: Setting the Epigenome Up for Success
9.3 Active DNA Demethylation: The Hunt for the `Demethylase´
9.4 Direct DNA Demethylation
9.5 Indirect Loss of DNA Methylation
9.5.1 Role of Cytosine Deamination in DNA Demethylation
9.5.2 Methylcytosine Oxidation-Based Demethylation Mechanisms
9.6 Chromatin Remodelling, DNA Replication, and Repair: The Epigenetic Triumvirate
9.7 Replication-Coupled Loss of DNA Methylation: Passive Demethylation
9.8 Resetting and Erasure of the Germline: A Barrier Against Transgenerational Inheritance
9.8.1 Demethylation During Preimplantation Development
9.9 Removing the Molecular Escapement Mechanism to Cell Fate and Aging by Modulation of DNA Methylation: How Cells Can Turn Ba...
References
10: Structure and Function of TET Enzymes
10.1 Introduction
10.2 Discovery of TET-Mediated 5mC Oxidation
10.2.1 TET-Mediated Iterative Oxidation of 5mC
10.2.2 TET-Dependent DNA Demethylation
10.2.3 Mechanisms and Processivity for TET-Mediated Oxidation Reaction
10.2.4 Oxidation of 5mrC-RNA and 6mA-DNA
10.3 Function of TET Enzymes
10.3.1 Distribution of TET Enzymes and 5mC Oxidation Derivatives
10.3.2 TET in ESCs and Cell Differentiation
10.3.3 TETs Mediate Epigenetic Reprogramming in Early Embryogenesis and PGC Development
10.3.4 TET Enzymes in Somatic Cell Reprogramming
10.3.5 TET Enzymes and Cancer
10.3.6 TET Enzymes in Neural System
10.4 Structure of TET Enzymes
10.4.1 Domain Structure of Human TET Enzymes
10.4.2 Crystal Structure of the TET2-5mC-DNA Complex
10.4.3 Crystal Structure of the NgTet1-5mC-DNA Complex
10.4.4 Structural Basis for Substrate Preference in TET-Mediated Oxidation
10.4.5 Crystal Structure of Algal TET Homologue CMD1 in Complex with VC and 5mC-DNA
10.5 Regulation of TET Enzymes
10.5.1 Inhibitors
10.5.2 Activators
10.5.3 Interacting Proteins
10.6 Concluding Remarks
References
11: Proteins That Read DNA Methylation
11.1 Introduction
11.2 The Methyl-CpG-Binding Domain Family
11.2.1 MeCP2
11.2.2 MBD1
11.2.3 MBD2
11.2.4 MBD3
11.2.5 MBD4
11.2.6 MBD5 and MBD6
11.3 SET- and RING-Associated (SRA) Domain
11.3.1 UHRF1
11.3.2 UHRF2
11.4 Transcription Factors
11.4.1 Kaiso and ZBTB38
11.4.2 CTCF
11.4.3 ZFP57
11.4.4 KLF4
11.4.5 EGR1 and WT1
11.4.6 bZIP
11.4.7 Homeodomain Proteins
11.5 Conclusion
References
12: Recent Advances on DNA Base Flipping: A General Mechanism for Writing, Reading, and Erasing DNA Modifications
12.1 Introduction
12.2 Base Flipping for Methylation of DNA Bases
12.2.1 Bacterial DNMTs (HhaI, TaqI, Dam, CcrM, and CamA)
12.2.2 Mammalian DNMTs (DNMT1, DNMT3A/3L)
12.2.3 Implications of DNA Methyltransferase Oligomers (DNMT3A/3L, DNMT3A/3B3, EcoP15I, CcrM, and MettL3-14)
12.2.4 Plant DNMTs
12.3 Base Flipping in Oxidative Modifications of Methylated Bases
12.3.1 Eukaryotic TET Enzymes
12.3.2 AlkB and Homologs
12.4 Base Flipping in the Recognition of Modified Bases
12.4.1 Eukaryotic SRA Domains
12.4.2 EcMcrB-N Homologs as 5mC and N6mA Readers
12.4.3 5mC and N6mA Readers Use Non-Base-Flipping Recognition
12.5 Base Flipping in Removing Modified and Unmodified Bases
12.5.1 Mammalian Thymine DNA Glycosylase (TDG)
12.5.2 Plant ROS1
12.5.3 Archaeon PabI Activity as Adenine DNA Glycosylase
12.6 Conclusions
References
13: The Role of DNA Methylation and DNA Methyltransferases in Cancer
13.1 Overview of Genetic and Epigenetic Alterations in Human Cancers
13.2 DNA Methyltransferases
13.3 Interplay Between DNA Methyltransferases and Histone Modifiers
13.4 CpG Islands
13.5 DNA Methylation
13.5.1 Tissue-Specific DNA Methylation
13.5.2 DNA Methylation as a Function of Aging
13.6 Mutations of Epigenetic Modifier Genes in Human Cancers
13.7 DNA Hypermethylation in Human Cancers
13.7.1 Tumor Stratification and DNA Methylation Marker Discovery Accelerated by International Consortia
13.7.2 Promoter DNA Hypermethylation
13.7.3 CpG Island Methylator Phenotypes (CIMPs) Stratify Tumor Subclasses
13.7.4 DNA Hypermethylation of Noncoding RNAs
13.7.5 DNA Hypomethylation
13.7.5.1 Repetitive Element DNA Hypomethylation
13.7.5.2 Partially Methylated Domains (PMDs)
13.7.6 Whole Genome Bisulfite Sequencing (WGBS) of Cancer Genomes
13.7.7 Gene Body DNA Methylation
13.7.8 Enhancer DNA Methylation
13.8 Liquid Biopsy Measurements of Cancer-Specific DNA Methylation
13.9 DNA Methylation as a Therapeutic Target
13.10 Concluding Remarks
References
14: DNA Methyltransferases and DNA Damage
14.1 Brief Summary of DNA Methyltransferases
14.2 DNA Methylation and Regulation of DNA Repair
14.2.1 Adenine Methylation and DNA Repair in Bacteria
14.2.2 DNA Methylation and Recombination
14.3 Direct Effects of DNA Methylation on DNA Damage
14.3.1 Effect of DNA Methylation of Mutation Rate via Cytosine Deamination
14.3.2 DNA Alkylation Damage Induction
14.3.3 DNA Demethylation and DNA Damage
14.4 Conclusion
References
15: Role of DNMTs in the Brain
15.1 Introduction
15.2 The Mammalian Brain
15.2.1 Developmental Principles of the Cerebral Cortex as the Seat of Higher Cognitive Functions
15.3 DNMT Expression in the Brain
15.4 DNMT Function in the Developing Brain: Neurogenesis
15.5 DNMT Function in the Developing Brain: Post-mitotic Neuronal Maturation
15.6 Role of DNMTs in Brain Function, Learning, and Memory
15.6.1 Functional Implications of DNMTs in Learning and Memory
15.6.2 DNMTs as Potential Mediators of Cell-Intrinsic Mechanisms for Memory Consolidation and Maintenance
15.7 DNMTs in Neurodevelopmental and Neuropsychiatric Diseases
15.8 DNMTs in Neuronal Aging
15.9 DNMTs in Neurodegeneration
15.9.1 Alzheimer´s Disease and Tauopathies
15.9.2 Huntington´s Disease
15.10 Role of DNMTs in Brain Cancer
15.10.1 Promoter Methylation
15.10.2 Methylation of Distal Regulatory Elements
15.10.3 Implications of Altered DNMT Expression and Targeting in Brain Cancer and Therapy Resistance
15.10.4 Crosstalk of DNMTs and miRNA-Mediated Translational Control
15.11 Conclusions
References
16: Current and Emerging Technologies for the Analysis of the Genome-Wide and Locus-Specific DNA Methylation Patterns
16.1 Introduction
16.1.1 DNA Methylation
16.2 Principles of DNA Methylation Detection
16.3 Global Methylation Content of a Sample
16.4 Whole Methylome Analyses
16.5 Genome-Wide Methylation Analyses Using NGS
16.5.1 Bisulfite-Based Methods
16.5.2 Affinity and Antibody-Based Enrichment Methods
16.5.3 Sequencing Approaches Using Methylation-Sensitive/Dependent Restriction Enzymes
16.5.4 Epigenotyping Arrays
16.6 Locus-Specific DNA Methylation Analysis
16.6.1 Amplicon Bisulfite Sequencing
16.6.2 Pyrosequencing
16.6.3 MALDI Mass Spectrometry
16.6.4 Methylation-Specific PCR and Its Quantitative Variations
16.7 DNA Methylation Analysis of Circulating Cell-Free DNA
16.8 Single-Cell DNA Methylation Analysis
16.9 Analysis of Cytosine Hydroxymethylation
16.10 Direct Readout of DNA Methylation
16.11 Combined Analysis of DNA Methylation and Other Epigenetic Modifications
16.11.1 Histone Modifications
16.11.2 Nucleosome Positioning
16.12 Conclusions
References
17: Inhibitors of DNA Methylation
17.1 How to Inhibit DNA Methyltransferases
17.2 Chemistry and Structure of DNMT Inhibitors
17.3 Potential Applications of DNMT Inhibitors
17.3.1 DNMTi Application in Cancers
17.3.1.1 Nucleoside Analogs
As Single Agent
Pro-drugs of Nucleoside Analogs
Nucleoside DNMTi in Combination with Other Drugs
With Other Epidrugs
With ``Classical´´ Chemo- and Immunotherapies
17.3.1.2 Non-nucleoside DNMTi
17.3.2 DNMTi Application in Neurological and Psychiatric Disorders
17.3.2.1 Memory Formation
17.3.2.2 Schizophrenia
17.3.2.3 Bipolar Disorders
17.3.2.4 Epilepsy
17.3.2.5 Post-traumatic Stress Disorder
17.3.2.6 Depression
17.3.2.7 X-Chromosome-Related Diseases and Autism Disorders
17.3.2.8 Parkinson´s and Alzheimer´s Diseases
17.3.2.9 Aging-Related Senescence and Amyotrophic Lateral Sclerosis
17.3.2.10 Neuronal Stem Cell
17.3.3 DNMTi Application in Cardiovascular Diseases
17.3.4 DNMTi Application in Other Human Pathologies
17.3.4.1 Obesity
17.3.4.2 Alcohol Addiction
17.3.4.3 Inflammation and Allergy
17.3.4.4 Infectious Diseases
Viral Infections
Bacterial Infections
Parasite Infections
17.3.4.5 Embryo Growth
17.3.5 DNMTi Application in Metabolite Production
17.3.6 DNMTi in Plants
17.4 Innovative Indirect and Combined Approaches to Better Target DNA Methylation
17.4.1 Methyl-CpG Binding Proteins: Nature and Probes
17.4.1.1 Methyl-CpG Binding Domain Proteins (MBD)
17.4.1.2 SET and RING Associated (SRA) Domain Proteins
17.4.1.3 Kaiso Proteins
17.4.2 Bifunctional Inhibitors Involving DNMTi
17.5 Limits and Hopes of DNMTi Applications and New Perspectives
References
18: Gene-Targeted DNA Methylation: Towards Long-Lasting Reprogramming of Gene Expression?
18.1 Introduction
18.2 Locus-Specific DNA Methylation Editing
18.2.1 Targeted DNA Methylation
18.2.2 Targeted DNA Demethylation
18.3 Sustained Transcriptional States upon DNA Methylation Editing
18.3.1 Long-Lasting Transcriptional Repression
18.3.2 Sustained Gene Re-expression
18.4 In Vivo Transcriptional Modulation via DNA Methylation Epigenetic Editing
18.5 Further Considerations
18.6 Conclusions
References
19: DNA Labeling Using DNA Methyltransferases
19.1 Introduction
19.2 Synthetic Cofactor Analogs for MTase-Directed Modification of DNA
19.3 MTase Activity with the Synthetic Cofactor Analogs
19.4 (Towards) Practical Implementation of MTase-Directed DNA Labeling in Genomic Research
19.4.1 MTase-Directed Labeling for General Manipulations and Analysis of DNA
19.4.2 DNA Labeling for Analysis of Particular DNA Sites or Sequences
19.4.2.1 Optical Mapping of DNA Sequences and Epigenetic States
19.4.2.2 Applications of MTase-Directed Labeling in Epigenomics
19.5 Cofactor-Independent MTase-Directed Labeling
19.6 Conclusions/Outlook
References