The DNA methyltransferases of mammals

Abstract

The biological significance of 5-methylcytosine was in doubt for many years, but is no longer. Through targeted mutagenesis in mice it has been learnt that every protein shown by biochemical tests to be involved in the establishment, maintenance or interpretation of genomic methylation patterns is encoded by an essential gene. A human genetic disorder (ICF syndrome) has recently been shown to be caused by mutations in the DNA methyltransferase 3B (DNMT3B) gene. A second human disorder (Rett syndrome) has been found to result from mutations in the MECP2 gene, which encodes a protein that binds to methylated DNA. Global genome demethylation caused by targeted mutations in the DNA methyltransferase-1 (Dnmt1) gene has shown that cytosine methylation plays essential roles in X-inactivation, genomic imprinting and genome stabilization. The majority of genomic 5-methylcytosine is now known to enforce the transcriptional silence of the enormous burden of transposons and retroviruses that have accumulated in the mammalian genome. It has also become clear that programmed changes in methylation patterns are less important in the regulation of mammalian development than was previously believed. Although a number of outstanding questions have yet to be answered (one of these questions involves the nature of the cues that designate sites for methylation at particular stages of gametogenesis and early development), studies of DNA methyltransferases are likely to provide further insights into the biological functions of genomic methylation patterns.

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

“…Methylation of CpG sites in the promoter region of a gene is commonly associated with repression of gene expression 10, 11, 12. DNA methylation occurs through the activity of DNA methyltransferases (DNMTs), particularly DNMT1 postdevelopment 13, 14, 15. Recently, DNA methylation has been shown to differentially regulate flow‐mediated endothelial gene expression through DNMT1,16, 17, 18, 19 although the role of DNA methylation in the regulation of arteriogenesis has not been explored.…”

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

“…Three DNA methyltransferase (DNMT) enzymes have been identified in eukaryotic cells (Bestor, 2000;Rountree et al, 2001). DNMT1 is generally considered to be a maintenance methylase, although it also has de novo methylase activity (Bestor, 2000;Robertson, 2002).…”

“…DNMT1 is generally considered to be a maintenance methylase, although it also has de novo methylase activity (Bestor, 2000;Robertson, 2002). Both DNMT3A and DNMT3B catalyse de novo methylation of DNA sequences (Li, 2002).…”

Induction of apoptosis of non-small cell lung cancer by a methylated oligonucleotide targeting survivin gene

“…In addition, it is reported that the effect of methylation-inducing gene silence may be greatly different from antisense oligonucleotide. [18][19][20] Theoretically, the epigenetic mark (DNA methylation) imposed is very stable in the genome and heritable through cell divisions. In our studies, we found that down-regulatory effects of SurKex1 on survivin expression persisted only up to passage 3 but weakened drastically in passage 4 after termination of SurKex1 transfection (Figure 2).…”

“…[16][17] DNA methylation is a critical epigenetic modification that silences gene transcription. [18][19] Yao et al 20 have devised a method to inhibit transcriptional initiation by constructing short methylated oligonucleotides which induce DNA methylation at specific loci. In this study, we used SurKex1, a methylated sense oligonucleotide designed emulating the method of Yao et al 20 , as an alternative strategy to target survivin and investigated its efficacy for the suppression of survivin expression and the consequent apoptotic induction potential in NCI-H460 cells.…”