Epigenetics and Disease (eBook)

Epigenetics and Disease 3
Preface 5
Contents 9
DNA Methylation and Cancer 11
1 Overview 11
2 Mechanisms of Silencing by DNA Methylation 12
3 DNA Methylation, Covalent Histone Modifications, and Histone Variants 14
3.1 Histone Variants 14
3.2 Posttranslational Histone Modifications 16
4 Epigenetic Switching in the Cancer Genome 17
5 Mechanisms of DNA Methylation Inheritance 19
6 Nucleosomes and DNA Methylation Patterns in Cancer 20
7 Epigenetic Regulation of miRNAs 21
8 DNA Methylation at CpG Poor Regions 22
9 Epigenetic Therapy 23
10 Conclusions and Future Directions 25
References 25
Genome-Wide Epigenetic Modifications in Cancer 34
1 Epigenetic Modifications in Healthy Tissue 34
1.1 Epigenetic Patterns in the Human Genome 34
1.2 DNA Methylation and Patterns of Gene Expression 36
1.3 DNA Methylation in Genomic Imprinting and X Inactivation 37
1.4 DNA Methylation and Genome Stability 37
2 Genome-Wide Epigenetic Alterations in Cancer 38
2.1 Hypermethylation of Candidate Genes 38
2.2 DNA Hypomethylation of Cancer Genomes 39
2.3 Epigenetic Changes in Imprinted Regions 39
2.4 Lessons Learned from Genome-Wide Approaches 39
2.5 Genetic vs. Epigenetic Alterations 41
3 Second Generation Methodologies for Epigenome-Wide Scans 42
3.1 Enrichment for Methylated CpG Sites 42
3.2 Methylome Analysis 44
4 Epigenetic Biomarkers 45
4.1 Epigenomic Profiles as Markers for Cancer Tissues 45
4.2 Epigenetic Markers for (Early) Detection of Cancer Cells and Screening 48
4.3 DNA Methylation Profiles as Marker for Risk Assessment, Tumor Progression, and Prognosis 49
4.4 Predicting Therapy Response by Epigenomic Profiles 49
4.5 Monitoring Epigenetic Therapies 50
5 Future Directions in Cancer Epigenetics 51
5.1 Understanding the Underlying Mechanisms of Epigenetic Regulation 51
5.2 Third Generation DNA Methylome Profiling 51
5.3 Integration of Epigenetic Markers in Clinical Settings 52
References 52
DNA Repair and the Control of DNA Methylation 59
1 Dynamic Stability of the ``DNA Methylation Code´´ 60
1.1 Fidelity of the Methylation System 61
1.2 Dynamics of Methylation States 61
2 Manifestation and Origin of DNA Methylation Instability 62
3 Enforcing Stability to DNA Methylation 65
4 Concluding Remark 70
References 71
Errors in Erasure: Links Between Histone Lysine Methylation Removal and Disease 77
1 Introduction 77
2 Lysine Demethylases Are Directly and Indirectly Associated with Both Oncogenic and Tumor-Suppressing Proteins 80
3 Proteins Required for Histone Deposition Are Linked to Development and Disease 84
4 Mislocalization of Cathepsin Proteases Is a Marker of Cancer 89
5 Conclusion 91
References 92
Histone Modifications in Cancer Biology and Prognosis 99
1 Introduction 100
2 Histone Modifications in Cancer Initiation 100
3 Histone Modifications as Clinical Tools 102
3.1 Alterations of Histone Modifications in Cancer 103
3.2 Histone Modifications as Prostate Cancer Prognostic Markers 103
3.3 Histone Modifications as General Prognostic Markers for Adenocarcinomas 105
3.4 Histone Modifications as Therapeutic Response Markers 108
4 Regulatory Mechanisms of Global Histone Modification Levels 109
5 Beyond Biomarkers: Future Outlook 111
References 112
Dynamics of Histone Lysine Methylation: Structures of Methyl Writers and Erasers 115
1 Introduction 115
2 Histone Lysine (K) Methyltransferases (HKMTs) 116
3 Structures of SET Domains 117
4 Structural Properties of Pre-SET and Post-SET Modules 118
5 Structure of Inhibitor Bound G9a and GLP SET Domains 120
6 Histone Lysine Specific Demethylase (LSD1) 121
7 Jumonji-Containing Lysine Demethylases 122
8 JMJD2A 124
9 PHF8 and KIAA1718 124
10 Perspective 126
References 126
Epigenetic Mechanisms of Mental Retardation 133
1 Introduction 133
1.1 Mental Retardation and Suppressive Histone Lysine Methylation 136
1.2 Mental Retardation and Activating Histone Lysine Methylation 138
1.3 Mental Retardation and Histone Lysine Acetylation 139
1.4 Mental Retardation and Histone Phosphorylation 141
1.5 Mental Retardation and DNA Methylation 141
1.6 Overcoming Difficulties Associated with Neuronal Heterogeneity 143
2 Prospectus 144
References 145
Histone and DNA Modifications in Mental Retardation 155
1 Introduction 155
2 DNA CpG Methylation in MR 156
2.1 The Roles of DNA Methyltransferases in MR 158
2.2 Reversibility of CpG Methylation 159
2.3 Methyl CpG ``Readers´´ 161
3 Covalent Histone Modifications and MR 163
3.1 Histone Acetyl Transferases/Histone Deacetylase 163
3.2 Histone Lysine Methyltransferases 165
3.3 Histone Lysine Demethylases 168
3.4 Histone Binding Factors (``Readers´´) 169
4 Noncovalent, ATP-Dependent Chromatin Remodeling in MR 171
5 Potential Therapeutic Implications 173
6 Concluding Remarks 173
References 174
HDAC Inhibitors and Cancer Therapy 182
1 Introduction 182
2 Opposing Activities of Histone Acetylation and Deacetylation 183
3 Classification of HDACs and Networks of Protein Regulation by Acetylation and Deacetylation 184
4 Rationale for Targeting HDACs for Anticancer Therapy 185
4.1 Role of HDACs in Tumor Suppressor Silencing 185
4.2 Role for HDACs in Deregulated Cell Growth and Survival Pathways 186
4.3 A Role for HDACs in Angiogenesis 188
5 HDAC Inhibitors 189
6 Molecular Antitumor Effects of HDAC Inhibitors 191
7 Clinical Experience with HDAC Inhibitors 193
8 Activities of HDAC Inhibitors in Hematological Malignancies 193
8.1 Cutaneous T-Cell Lymphoma 193
8.2 Hodgkins Lymphoma 194
8.3 AML/MDS and Other Acute Hemeatological Malignancies 194
8.4 Multiple Myeloma 195
9 Activity of HDAC Inhibitors in Solid Tumors 196
10 Challenges in Developing HDAC Inhibitors for Anticancer Therapy and Future Outlook 197
References 198
Epigenetic Mechanisms in Acute Myeloid Leukemia 203
1 Introduction 204
2 Epigenetic Regulation by Histone Methyltransferases 204
2.1 Mixed-Lineage Leukemia 1 204
2.2 Targeting of MLL-Fusion Complexes 205
2.3 Enhancing Transcriptional Elongation 206
2.4 A Role for PHD Fingers in Leukemia 207
3 NSD-Fusions Target Histone Methyltransferase Activity 208
4 Epigenetic Regulation by Histone Acetyltransferases 209
5 Indirect Epigenetic Deregulation 210
6 Aberrant Promoter DNA Methylation 212
7 MicroRNAs in AML 213
8 Epigenetic Therapy of AML 214
References 216
The Liver-Specific MicroRNA miR-122: Biology and Therapeutic Potential 226
1 Introduction 226
1.1 History of miRNAs: What Are miRNAs and How Were They Found 226
1.2 The Multistep Process of miRNA Biogenesis 227
1.3 miRNAs Silence Target mRNAs Through an Antisense Mechanism 227
1.4 miRNA-Mediated Gene Silencing Is Reversible 228
2 miR-122 and Cancer 230
2.1 Prelude: The hcr RNA and Hepatocellular Carcinoma in Woodchucks 230
2.2 Misexpression of miR-122 in HCC 230
2.3 miR-122 as a Tumor Suppressor: Evidence from In Vitro and In Vivo Mechanistic Studies 232
3 miR-122 and HCV 233
3.1 miR-122 Has Stimulatory Effects on Accumulation and Translation of HCV RNA 233
3.2 Silencing of miR-122 in the Liver of Rodents and Nonhuman Primates 235
3.3 miR-122 Status in Patients with Chronic Hepatitis C 236
4 Outlook 238
References 239
Transcriptional Regulatory Networks in Embryonic Stem Cells 244
1 Transcriptional Regulation 245
1.1 The Transcriptome and Cell State 245
1.2 Dissecting Transcriptional Regulation 245
1.3 From Model Organisms to Complex Vertebrates 246
2 Unraveling the Transcriptional Regulatory Networks in ESCs 247
2.1 Master Regulators in ESC 247
2.2 Mapping the Core Transcriptional Regulatory Network in ESCs 248
2.3 Expanding the ESC Transcriptional Regulatory Networks 249
2.4 Wiring Components of Signaling Pathways to the Core Transcriptional Regulatory Network 250
2.5 Enhanceosomes in ESCs 252
2.6 Identification of Novel Nodes in the ESC Transcriptional Regulatory Networks 252
3 From Pluripotent Stem Cell to Induced Pluripotent Stem Cell Networks 254
3.1 Transcription Factor-Mediated Reversion of Terminal Cell Fate 254
3.2 Dissecting the Mechanism of Factor-Mediated Reprogramming 254
3.3 iPSC Transcriptome Highlights Potential Difference in Pluripotency Status 255
4 Conclusions 255
References 255
Small Molecules in Cellular Reprogramming and Differentiation 258
1 Introduction 258
2 Small Molecules in Inducing Pluripotency 259
2.1 Epigenetic Modifiers in Inducing Pluripotent Cells 259
2.2 Signaling Modulators in Reprogramming 262
3 Small Molecules in Directed Differentiation 263
3.1 Small Molecules for Cardiac Induction 264
3.2 Small Molecules for Endoderm Induction 265
3.3 Small Molecules for Neural Induction 266
4 Perspectives 267
References 267
Index 272