DNA methylation and epigenetic inheritance.
Mammalian cell lines silence genes at low frequency by the methylation of promoter sequences. These silent genes can be reactivated at high frequency by the demethylating agent 5-azacytidine (5-aza-CR). The inactive and active epigenetic states of such genes are stably inherited. A method for silencing genes is now available. It involves treatment of permeabilized cells with 5-methyl deoxycytidine triphosphate (5-methyl dCTP) which is incorporated into DNA. The methylation of promoter sequences has been confirmed using the bisulfite genomic sequencing procedure. Methylated oligonucleotides homologous to promoter sequences might be used to specifically target and silence given genes, but results so far have not been conclusive. Treatments that silence or reactivate genes by changing DNA methylation can be referred to as epimutagens, as distinct from mutagens that act by changing DNA sequences. The epimutagen 5-aza-CR reactivates genes but has little mutagenic activity, whereas standard mutagens (such as ethyl methane sulfonate and ultraviolet light) have little reactivation activity. Nevertheless, much more information is required about the effects of DNA-damaging agents in changing DNA methylation and gene activity and also about the role of epimutations in tumor progression.
Holliday
Robin
R
Sydney Laboratory, CSIRO Molecular Science, P.O. Box 184, North Ryde, New South Wales 2113, Australia.
Ho
Thu
T
D000818:Animals; D001374:Azacitidine / Q000378:metabolism; D019175:DNA Methylation; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D020868:Gene Silencing; D040582:Inheritance Patterns; D009153:Mutagens / Q000494:pharmacology; D011401:Promoter Regions, Genetic
D003845:Deoxycytosine Nucleotides; D009153:Mutagens; C034817:5-methyldeoxycytidine triphosphate; D001374:Azacitidine