ABSTRACT
Contents 3.1 Introduction ............................................................................................ 38 3.2 Mechanism of DNA methylation ........................................................ 39 3.3 Mammalian DNA methyltransferases ............................................... 40 3.4 DNA methyltransferase 1 ..................................................................... 41 3.5 DNA methyltransferase 2 ..................................................................... 42 3.6 The Dnmt3 family: de novo methyltransferases ............................... 42 3.7 Dnmt3a and Dnmt3b possess distinct functions during
embryogenesis........................................................................................ 43 3.8 Alternate isoforms of Dnmt3a and Dnmt3b ...................................... 44 3.9 Dnmt3L ................................................................................................... 45 3.10 Methylated-DNA binding proteins ..................................................... 45 3.11 DNA methylation and chromatin structure ...................................... 46 3.12 Crosstalk between DNA methylation and other epigenetic
systems .................................................................................................... 48 3.13 DNA methylation and chromatin remodeling .................................. 48 3.14 DNA methylation and posttranslational modifications (PTMs)
of histones ............................................................................................... 49 3.15 DNA methylation and siRNA-mediated transcriptional gene
silencing (TGS) ....................................................................................... 50 3.16 RNA-directed DNA methylation in mammals? ............................... 51 3.17 DNA methyltransferases and DNA repair ........................................ 52 3.18 What next? .............................................................................................. 53 References ......................................................................................................... 53
3.1 Introduction 5-Methylcytosine (5mC) was first detected in mammalian DNA 60 years ago1 and within six years, it was demonstrated that the only dinucleotide with significant 5mC content was 5mC,G.2,3 It took almost another decade to determine that cytosine residues were enzymatically methylated after incorporation into DNA, establishing the basis for epigenetic modulation of gene expression.4,5 The first demonstrations that inhibition of DNA methylation could induce differentiation of cultured cells were published in the late 1970s.6-8 Since then, it has become increasingly clear that DNA methylation plays a number of important roles in cellular homeostasis and regulation of normal mammalian development. Methylation of DNA promotes genomic stability through repression of mitotic recombination and transposition, assuring proper chromatid segregation and maintenance of higher-order heterochromatin structure.9-11 Genomic methylation patterns also play a crucial role during embryogenesis, leading to temporal transcriptional repression of critical developmental programs during cellular differentiation through its ability to regulate chromatin structure.12-14 Additionally, DNA methylation is integral to the processes of genomic imprinting and gene dosage compensation in females through inactivation of one X chromosome.15,16 A variety of tumors exhibit aberrant DNA methylation patterns. The most common change is an early global loss or reduction in DNA methylation, that is hypomethylation.17-20 This is followed by localized promoter hypermethylation of tumor-suppressor genes (see Reference 21 for a comprehensive review of epigenetic events associated with cancer).
