PubMed · 12728239
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
Vijayender Bhalla, Ram P Bajpai, Lalit M Bharadwaj. 2003. DNA electronics.. https://doi.org/10.1038/sj.embor.embor834
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
O6-methylguanine-DNA methyltransferase (MGMT) repairs the cytotoxic and mutagenic O6-alkylguanine produced by alkylating agents such as chemotherapeutic agents and mutagens. Recent studies have shown that in a subset of tumors, MGMT expression is inversely linked to hypermethylation of the CpG island in the promoter region; however, how the epigenetic silencing mechanism works, as it relates to hypermethylation, was still unclear. To understand the mechanism, we examined the detailed methylation status of the whole island with bisulfite-sequencing in 19 MGMT non-expressed cancer cell lines. We found two highly methylated regions in the island. One was upstream of exon 1, including minimal promoter, and the other was downstream, including enhancer. Reporter gene assay showed that methylation of both the upstream and downstream regions suppressed luciferase activity drastically. Chromatin immunoprecipitation assay revealed that histone H3 lysine 9 was hypermethylated throughout the island in the MGMT negative line, whereas acetylation on H3 and H4 and methylation on H3 lysine 4 were at significantly high levels outside the minimal promoter in the MGMT-expressed line. Furthermore, MeCP2 preferentially bound to the CpG-methylated island in the MGMT negative line. Given these results, we propose a model for gene silencing of MGMT that is dependent on the epigenetic state in cancer.
Explore the source record for details and available documents.
Differences in the regional substitution patterns in the human genome created patterns of large-scale variation of base composition known as genomic isochores. To gain insight into the origin of the genomic isochores, we develop a maximum-likelihood approach to determine the history of substitution patterns in the human genome. This approach utilizes the vast amount of repetitive sequence deposited in the human genome over the past approximately 250 Myr. Using this approach, we estimate the frequencies of seven types of substitutions: the four transversions, two transitions, and the methyl-assisted transition of cytosine in CpG. Comparing substitutional patterns in repetitive elements of various ages, we reconstruct the history of the base-substitutional process in the different isochores for the past 250 Myr. At around 90 MYA (around the time of the mammalian radiation), we find an abrupt fourfold to eightfold increase of the cytosine transition rate in CpG pairs compared with that of the reptilian ancestor. Further analysis of nucleotide substitutions in regions with different GC content reveals concurrent changes in the substitutional patterns. Although the substitutional pattern was dependent on the regional GC content in such ways that it preserved the regional GC content before the mammalian radiation, it lost this dependence afterward. The substitutional pattern changed from an isochore-preserving to an isochore-degrading one. We conclude that isochores have been established before the radiation of the eutherian mammals and have been subject to the process of homogenization since then.