Main description:

NA methylation has bewildered molecular biologists since Hotchkiss discovered it almost six decades ago (Hotchkiss RDJ. Biol Cem 1948; 175:315-332). The fact that the chemical structure of our D genome consists of two components that are covalently bound, the genetic information that is replicated by the DNA replication machinery ana DNA methylation that is maintainea by independent enzymatic machinery, has redictably stimulated the imagination and curiosity of generations of mo Edular biologists. An obvious question was whether DNA methylation was a bearer of additional information to the genetic information and what was the nature of this information? It was tempting to speculate that DNA me thylation applied some form of control over programming of the genome s expression profile. Once techniques to probe the methylation profile of whole genomes as well as specific genes became available, it became clear that DNA methylation patterns are gene and tissue specific and that patterns of gene expression correlate with patterns of methylation. DNA methylation pat terns emerged as the only component of the chemical structure of DNA that exhibited tissue and cell specificity. This data seemingly provided an attrac tively simple explanation for the longstanding dilemma of how could one identical genome manifest itself in so many different forms in multicellular organisms? The DNA methylation pattern has thus become the only known factor to confer upon DNA a unique cellular identity.

Contents:

Preface ................................................................................................ xiii 1. DNA Methylation: Three Decades in Search of Function ...................... 1 Aharon Razin DNA Methylation in Prokaryotes.......................................................... 1 DNA Methylation in Eukaryotes ........................................................... 2 Methylation and Embryogenesis ............................................................ 2 DNA Methylation and Imprinting ........................................................ 4 DNA Methylation in Gene Silencing .................................................... 4 DNA Methylation and Disease.............................................................. 5 Reflections ............................................................................................. 8 2. Epigenetic Mechanisms of Gene Regulation: Relationships between DNA Methylation, Histone Modification, and Chromatin Structure ..................................................................... 13 Keith D. Robertson The Mammalian DNA Methyltransferases (DNMTs) ......................... 14 Interaction between DNMTs and Other Proteins ............................... 16 DNA Methylation and DNA Replication ............................................ 20 Links between DNA Methylation and Histone Modification .............. 20 DNA Methylation and Histone Methylation ...................................... 21 DNMTs As Transcriptional Corepressors ........................................... 22 DNA Methylation and Chromatin Remodeling .................................. 24 3. DNA Hypo- vs. Hypermethylation in Cancer: Tumor Specificity, Tumor Progression, and Therapeutic Implications .............................. 31 Melanie Ehrlich and GuanchaoJiang Are There Tumor-Specific DNA Hypomethylation Profiles Like the Tumor-Specific DNA Hypermethylation Profiles? .................... 32 Is There a Relationship between Cancer-Associated DNA, Hypomethylation and DNA Hypermethylation? ............................. 34 Is DNA Hypomethylation, Like DNA Hypermethylation, Sometimes Associated with Tumor Progression? .............................. 35 Might There Be Deleterious Consequences of Introducing DNA Hypomethylation in the Genome As a Cancer Therapy? ................. 37 4. DNA Methylation in Urological Cancers ............................................. 42 Wolfgang A. Schulz and Hans-Helge Seifert An Overview of Urological Cancers ..................................................... 42 A Description of DNA Methylation Changes in Urological Malignancies .............................................................. 44 A Global View of DNA Methylation Alterations in Urological Cancers ...................................................................... 47 Causes of Altered DNA Methylation in Urological Cancers ................ 48 Consequences of Altered DNA Methylation in Urological Cancers ....... 50 DNA Methylation in Diagnosis and Therapy of Urological Cancers ...... 51 Szyf MIU Front Matter 9/15/04, 2:29 PM 5 5. DNA Methylation in Colorectal Cancer ............................................... 59 Jeremy R. Jass, Vicki L.J. Whitehall, Joanne Young and Barbara A. Leggett Relevance of Familial Models of Colorectal Cancer to Sporadic Neoplasia ...................................................................... 60 DNA Microsatellite Instability ............................................................ 60 Mechanisms Underlying Microsatellite Instability in Colorectal Cancer .........................