CpG methylation-dependent repression of the human O6-methylguanine-DNA methyltransferase gene linked to chromatin structure alteration.
作者： K. K. Bhakat , S. Mitra
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摘要: The mechanism of inactivation the O6-methylguanine-DNA methyltransferase (MGMT), responsible for repair mutagenic and cytotoxic O6-alkylguanine, in Mex- tumor cells, is not completely understood. We have examined role CpG methylation human MGMT promoter a luciferase (luc) reporter plasmid associated alteration chromatin structure. Methylation 16% sequences flanking with HpaII methylase reduced activity by 10-12-fold, while all sites, including those luc coding sequence, as well sequence blocked expression completely. Repression due to partial but complete could be reversed histone deacetylase inhibitor trichostatin A (TSA). However, 5-azacytidine, which reverses methylation, TSA, reactivate silent gene HeLa MR cells. Furthermore, immunoprecipitation (ChIP) assay showed level acetylation H4 bound methylated compared non-methylated promoter. These results suggest that repression cells requires both neighboring regions gene, resulting inactive, condensed state gene.
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