DNA methylation
From Freepedia
DNA methylation is a type of chemical modification which involves the addition of a methyl group to the number 5 carbon of the cytosine pyrimidine ring.
DNA methylation is probably universal in vertebrates and is part of the epigenetic code, referring to the heritable change in gene function without change in DNA sequence. In humans, approximately 1% of DNA bases undergo DNA methylation. In adult somatic tissues, DNA methylation typically occurs in a CpG dinucleotide context. Between 60-70% of all CpG's are methylated. Unmethylated CpG's are grouped in clusters called "CpG islands" that are present in the 5' regulatory regions of many genes. In many disease processes such as cancer, gene promoter CpG islands acquire abnormal hypermethylation which results in heritable transcriptional silencing. Reinforcement of the transcriptionally silent state is mediated by proteins that can bind methylated CpG's, named methyl-CpG binding proteins. These proteins recruit histone deacytelases and other chromatin remodelling proteins that can modify histones, thereby forming compact, inactive chromatin termed heterochromatin. This link between DNA methylation and chromatin structure is very important. In particular, loss of Methyl-CpG-binding Protein 2 (MeCP2) has been implicated in Rett syndrome and Methyl-CpG binding domain protein 2 (MBD2) mediates the transcriptional silencing of hypermethylated genes in cancer.
In humans, the process of DNA methylation is carried out by three enzymes, DNA methyltransferase 1, 3a, and 3b (DNMT1, DNMT3a, DNMT3b). It is thought that DNMT3a and DNMT3b are the de novo methyltransferases that set up DNA methylation patterns early in development. DNMT1 is the proposed maintenance methyltransferase that is responsible for copying DNA methylation patterns to the daughter strands during DNA replication. DNMT3L is a protein that is homologous to the other DNMT's but has no catalytic activity. Instead, DNMT3L assists the de novo methyltransferases by increasing their ability to bind to DNA and stimulating their activity.
Since many tumor suppressor genes are silenced by DNA methylation during carcinogenesis, there have been attempts to reexpress these genes by inhibiting the DNMT's. 5-aza-2'-deoxycytidine (decitabine) is a nucleoside analog that inhibits DNMT's by trapping them in a covalent complex on DNA by preventing the ß-elimination step of catalysis, thus resulting in the enzymes' degradation. However, for decitabine to be active, it must be incorporated into the genome of the cell which can cause mutations in the daughter cells if the cell does not die. Additionally, decitabine is toxic to the bone marrow which limits the size of its therapeutic window. These pitfalls have led to the development of antisense RNA therapies that target the DNMT's by degrading their mRNA's and preventing their translation. However, it is currently unclear if targeting DNMT1 alone is sufficient to reactivate tumor suppressor genes silenced by DNA methylation.
