Epigenetics and Disease: Pharmaceutical Opportunities (Progress in Drug Research, Vol. 67)

Epigenetics has emerged recently as an important area of molecular biological studies. Epigenetic modifications lead to potentially heritable but reversible alterations in the expression of genes that determine cell fate. Epigenetic misregulation is thus often linked to degenerative diseases, cancer and neuronal disorders. Recent biomedical interest in this regulatory system stems from the fact that epigenetic, in contrast to genetic, alterations are in principle amenable to pharmacological intervention. A few epigenetically active drugs, for example histone deacetylase inhibitors (HDACi) and DNA methyltransferase (DNMT) inhibitors, have been approved by FDA for treatment of cancers such as CTCL, MDS, and AML. This volume explores the scientific background for clinical applications of epigenetically active drugs. Included are descriptions of epigenetic controls over gene expression, the post-transcriptional silencing of genes by RNA interference (RNAi) and microRNAs, as well as new findings from stem cell research which are relevant to pharmacological applications. Epigenetics and Disease: Pharmaceutical Opportunities (Progress in Drug Research, Vol. 67)......Page 1 front-matter......Page 2 Epigenetics and Disease......Page 4 © Springer Basel AG 2011......Page 5 Preface......Page 6 Contents......Page 10 1 Overview......Page 12 2 Mechanisms of Silencing by DNA Methylation......Page 13 3.1 Histone Variants......Page 15 3.2 Posttranslational Histone Modifications......Page 17 4 Epigenetic Switching in the Cancer Genome......Page 18 5 Mechanisms of DNA Methylation Inheritance......Page 20 6 Nucleosomes and DNA Methylation Patterns in Cancer......Page 21 7 Epigenetic Regulation of miRNAs......Page 22 8 DNA Methylation at CpG Poor Regions......Page 23 9 Epigenetic Therapy......Page 24 References......Page 26 1.1 Epigenetic Patterns in the Human Genome......Page 36 1.2 DNA Methylation and Patterns of Gene Expression......Page 38 1.4 DNA Methylation and Genome Stability......Page 39 2.1 Hypermethylation of Candidate Genes......Page 40 2.4 Lessons Learned from Genome-Wide Approaches......Page 41 2.5 Genetic vs. Epigenetic Alterations......Page 43 3.1 Enrichment for Methylated CpG Sites......Page 44 3.2 Methylome Analysis......Page 46 4.1 Epigenomic Profiles as Markers for Cancer Tissues......Page 47 4.2 Epigenetic Markers for (Early) Detection of Cancer Cells and Screening......Page 50 4.4 Predicting Therapy Response by Epigenomic Profiles......Page 51 4.5 Monitoring Epigenetic Therapies......Page 52 5.2 Third Generation DNA Methylome Profiling......Page 53 References......Page 54 DNA Repair and the Control of DNA Methylation......Page 62 1 Dynamic Stability of the ``DNA Methylation Code ́ ́......Page 63 1.2 Dynamics of Methylation States......Page 64 2 Manifestation and Origin of DNA Methylation Instability......Page 65 3 Enforcing Stability to DNA Methylation......Page 68 4 Concluding Remark......Page 73 References......Page 74 1 Introduction......Page 80 2 Lysine Demethylases Are Directly and Indirectly Associated with Both Oncogenic and Tumor-Suppressing Proteins......Page 83 3 Proteins Required for Histone Deposition Are Linked to Development and Disease......Page 87 4 Mislocalization of Cathepsin Proteases Is a Marker of Cancer......Page 92 5 Conclusion......Page 94 References......Page 95 Histone Modifications in Cancer Biology and Prognosis......Page 102 2 Histone Modifications in Cancer Initiation......Page 103 3 Histone Modifications as Clinical Tools......Page 105 3.2 Histone Modifications as Prostate Cancer Prognostic Markers......Page 106 3.3 Histone Modifications as General Prognostic Markers for Adenocarcinomas......Page 108 3.4 Histone Modifications as Therapeutic Response Markers......Page 111 4 Regulatory Mechanisms of Global Histone Modification Levels......Page 112 5 Beyond Biomarkers: Future Outlook......Page 114 References......Page 115 1 Introduction......Page 118 2 Histone Lysine (K) Methyltransferases (HKMTs)......Page 119 3 Structures of SET Domains......Page 120 4 Structural Properties of Pre-SET and Post-SET Modules......Page 121 5 Structure of Inhibitor Bound G9a and GLP SET Domains......Page 123 6 Histone Lysine Specific Demethylase (LSD1)......Page 124 7 Jumonji-Containing Lysine Demethylases......Page 125 9 PHF8 and KIAA1718......Page 127 References......Page 129 1 Introduction......Page 136 1.1 Mental Retardation and Suppressive Histone Lysine Methylation......Page 139 1.2 Mental Retardation and Activating Histone Lysine Methylation......Page 141 1.3 Mental Retardation and Histone Lysine Acetylation......Page 142 1.5 Mental Retardation and DNA Methylation......Page 144 1.6 Overcoming Difficulties Associated with Neuronal Heterogeneity......Page 146 2 Prospectus......Page 147 References......Page 148 1 Introduction......Page 158 2 DNA CpG Methylation in MR......Page 159 2.1 The Roles of DNA Methyltransferases in MR......Page 161 2.2 Reversibility of CpG Methylation......Page 162 2.3 Methyl CpG ``Readers ́ ́......Page 164 3.1 Histone Acetyl Transferases/Histone Deacetylase......Page 166 3.2 Histone Lysine Methyltransferases......Page 168 3.3 Histone Lysine Demethylases......Page 171 3.4 Histone Binding Factors (``Readers ́ ́)......Page 172 4 Noncovalent, ATP-Dependent Chromatin Remodeling in MR......Page 174 6 Concluding Remarks......Page 176 References......Page 177 1 Introduction......Page 186 2 Opposing Activities of Histone Acetylation and Deacetylation......Page 187 3 Classification of HDACs and Networks of Protein Regulation by Acetylation and Deacetylation......Page 188 4.1 Role of HDACs in Tumor Suppressor Silencing......Page 189 4.2 Role for HDACs in Deregulated Cell Growth and Survival Pathways......Page 190 4.3 A Role for HDACs in Angiogenesis......Page 192 5 HDAC Inhibitors......Page 193 6 Molecular Antitumor Effects of HDAC Inhibitors......Page 195 8.1 Cutaneous T-Cell Lymphoma......Page 197 8.3 AML/MDS and Other Acute Hemeatological Malignancies......Page 198 8.4 Multiple Myeloma......Page 199 9 Activity of HDAC Inhibitors in Solid Tumors......Page 200 10 Challenges in Developing HDAC Inhibitors for Anticancer Therapy and Future Outlook......Page 201 References......Page 202 Epigenetic Mechanisms in Acute Myeloid Leukemia......Page 208 2.1 Mixed-Lineage Leukemia 1......Page 209 2.2 Targeting of MLL-Fusion Complexes......Page 210 2.3 Enhancing Transcriptional Elongation......Page 211 2.4 A Role for PHD Fingers in Leukemia......Page 212 3 NSD-Fusions Target Histone Methyltransferase Activity......Page 213 4 Epigenetic Regulation by Histone Acetyltransferases......Page 214 5 Indirect Epigenetic Deregulation......Page 215 6 Aberrant Promoter DNA Methylation......Page 217 7 MicroRNAs in AML......Page 218 8 Epigenetic Therapy of AML......Page 219 References......Page 221 1.1 History of miRNAs: What Are miRNAs and How Were They Found......Page 232 1.3 miRNAs Silence Target mRNAs Through an Antisense Mechanism......Page 233 1.4 miRNA-Mediated Gene Silencing Is Reversible......Page 234 2.2 Misexpression of miR-122 in HCC......Page 236 2.3 miR-122 as a Tumor Suppressor: Evidence from In Vitro and In Vivo Mechanistic Studies......Page 238 3.1 miR-122 Has Stimulatory Effects on Accumulation and Translation of HCV RNA......Page 239 3.2 Silencing of miR-122 in the Liver of Rodents and Nonhuman Primates......Page 241 3.3 miR-122 Status in Patients with Chronic Hepatitis C......Page 242 4 Outlook......Page 244 References......Page 245 Transcriptional Regulatory Networks in Embryonic Stem Cells......Page 250 1.2 Dissecting Transcriptional Regulation......Page 251 1.3 From Model Organisms to Complex Vertebrates......Page 252 2.1 Master Regulators in ESC......Page 253 2.2 Mapping the Core Transcriptional Regulatory Network in ESCs......Page 254 2.3 Expanding the ESC Transcriptional Regulatory Networks......Page 255 2.4 Wiring Components of Signaling Pathways to the Core Transcriptional Regulatory Network......Page 256 2.6 Identification of Novel Nodes in the ESC Transcriptional Regulatory Networks......Page 258 3.2 Dissecting the Mechanism of Factor-Mediated Reprogramming......Page 260 References......Page 261 1 Introduction......Page 264 2.1 Epigenetic Modifiers in Inducing Pluripotent Cells......Page 265 2.2 Signaling Modulators in Reprogramming......Page 268 3 Small Molecules in Directed Differentiation......Page 269 3.1 Small Molecules for Cardiac Induction......Page 270 3.2 Small Molecules for Endoderm Induction......Page 271 3.3 Small Molecules for Neural Induction......Page 272 References......Page 273 Index......Page 278