DNA Methylation and Cellular Differentiation

Abstract

I. DNA Methylation and Cell Differentiation: An Overview.- A. Introduction.- B. What New Properties Does Methylation Confer on DNA?.- C. The Origin and Maintenance of Methyl Cytosine in DNA.- D. Differentiation: The Problem Posed.- E. Genome Modifications Which Can Be Associated with Differentiation.- 1. The Insect Type of Differentiation.- 2. Is the Determined State Reversible?.- 3. The Vertebrate Type of Differentiation.- 4. Modifications of the Genome.- 5. Mobile Genetic Elements.- a) Examples of Mobile Genetic Elements in Com.- b) The Discovery of a Mutable Gene.- II. DNA Methylation and Transposable Genetic Elements.- A. Discovery of Enzymatic Methylation of DNA.- B. The First Demonstrated Role of DNA Methylation: Restriction-Modification Systems in Bacteria.- C. Hypotheses for Roles of Methylation in Eukaryotes.- D. Transposable Genetic Elements.- 1. Flagellar Phase Variation of Salmonella.- 2. Insertion Sequences and Transposons.- a) Insertion Sequences.- b) Transposons in Bacteria.- c) Transposons in Eukaryotes.- 1. A Transposable Element in Yeast, Ty.- 2. Transposable Elements in Drosophila.- 3. Retroviruses.- 4. Alu Family of Sequences in the Human Genome.- III. Differentiating Systems and Their Methylation Patterns.- A. Differentiation of the Hemopoietic System and Organization of Hemoglobin Genes..- B. Methylation Patterns of Hemoglobin Genes.- 1. A Method for Locating Single CpG Sites by the Use of Two Restriction Endo- nucleases Which Are Isoschizomers.- 2. The Genes of the Beta Cluster Which Function in a Reticulocyte Are Undermethy- lated.- 3. Tissue Specific DNA Methylation Occurs in the Cluster of Rabbit Beta-Like Globin Genes.- 4. The Alpha-Globin Gene Cluster in the Chicken andXenopus.- C. Differentiation of Lymphocytes and the Role of Methylation.- D. Suppression of Integrated Viral Genomes in Cells by DNA Methylation.- 1. Small DNA Viruses.- 2. Inactivation of Retroviral Genomes by DNA Methylation.- E. The Vitellogenin Genes in Xenopus Are Methylated, But Can Be Expressed Without a Detectable Change in the Pattern.- F. Integrated Retroviruses Are Methylated Early in Development.- G. Suppression of Metallothionein Genes by Methylation.- H. Other Genes That Are Suppressed by Methylation.- I. Correlation Between DNase I Sensitivity of Chromatin and Cytosine Methylation.- J. The Hpall Sites in an Ovalbumin Gene.- K. The 5' End of the Rat Albumin Gene Is Undermethylated in Cells in Which It Is Expressed.- L. Methylation of Human Growth Hormone and Somatotropin Genes.- M. Methylation of Ribosomal Genes.- IV. DNA Methylation and the Inactive X Chromosome of Mammals.- A. A Brief History of X Chromosome Inactivation Studies.- B. A New Methylation Model.- V. Mechanisms of Suppression by DNA Methylation.- A. Expression of the Late Viral Protein of SV-40 (VP-1) Is Reduced by Methylation at One Hpall Site.- B. Transcription of a Cloned Adenovirus Gene Is Inhibited by in vitro Methylation.- C. Transcription of a Cloned Human Gamma Globin Gene Is Inhibited by Methylation at the 5' Region Flanking the Structural Gene.- D. The Mechanism by Which Methylated CpG Sites Inhibit Transcription.- E. How Are Methylation Patterns Established and Maintained?.- F. The Specificity of Methylases and the Maintenance of Methylation Patterns.- 1. Prokaryotic Type II Methylases.- 2. Type I and Type III Methylases.- G. Properties of Eukaryotic Methylases.- H. The Maintenance of Methylation Patterns Imposed in vitro.- I. Deletion of Methylation Patterns During Differentiation.- VI. Evolution, Stability and Regulation of Methylation Patterns.- A. The Evolutionary Aspects of DNA Methylation.- 1. 5-Methylcytosine Residues Are Hotspots for Mutation in Bacteria.- 2. Are 5-Methylcytosine Residues Hotspots for Mutation in Eukaryotes?.- B. DNA Methylation and Repair.- C. How Stable Is a Pattern of Methylation?.- D. Overview on the Role of DNA Methylation.- E. An Hypothesis for the Control of Methylation Patterns.- F. A Pyramid of Controls in Vertebrate Cells.- References.