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Methylation-Based Epigenetic Control May Be Short-Lived, Research Suggests

NEW YORK (GenomeWeb News) – New research is revealing the transient nature of some epigenetic regulation.
 
Researchers at the European Molecular Biology Laboratory and elsewhere evaluated the methylation-based regulation of specific promoters in breast cancer cells. Their work suggests nucleotides within at least five promoters, including an estrogen-related promoter, are cyclically methylated and demethylated. These results, which will be published this week in Nature, indicate that some aspects of epigenetic regulation may be more transient than previously believed.
 
“We observed that, unlike assumed for a long time, methylation can act on a very short timescale,” Sara Kangaspeska, a researcher at EMBL in Heidelberg, Germany and co-lead author on the paper, said in a statement. “The results challenge our understanding of epigenetics as a means to regulate gene expression permanently.”
 
In general, epigenetic regulation involves changes in chromatin structure that influence gene expression. For example, DNA methylation may play a role in epigenetics by blocking transcriptional machinery and keeping it from accessing DNA. In particular, methylation can turn off or silence transcription by affecting CpG dinucleotides, stretches of DNA that contain a cytosine nucleotide followed by a guanine nucleotide, which often appear at the transcription start site.
 
Kangaspeska and her colleagues used GST-pulldowns to assess the methylation state of estrogen-responsive promoters in a human breast cancer adenocarcinoma cell line over time. They found that adding estrogen led to methylation and demethylation cycles for the estrogen-receptive promoter, but not for another, control promoter. They confirmed these results using endpoint PCR and quantitative PCR to evaluate methylation at CpG nucleotides.
 
But when they removed estrogen or treated the cells with a compound called doxorubicin, the generic version of the chemotherapy drug Adriamycin, DNA methylation changed. For example, about 45 minutes after they added doxorubicin, the researchers saw a decrease in methylation of the estrogen-receptive promoter they were evaluating. That seems to be because doxorubicin incorporates itself into GC-rich stretches of DNA and interferes with the action of the methyltransferase enzyme that facilitates methylation.
 
The researchers also looked at how gene expression changed in another breast cancer cell line in response to the doxorubicin-related changes in methylation. Whereas the promoters of interest were not expressed in the absence of doxorubicin, they did detect some expression of genes regulated by these promoters when the drug was added.
 
Overall, these results may provide clues about how epigenetic changes, particularly those related to methylation, arise in cells. “Transitory modifications in the methylation status of promoters may provide a mechanistic link between transcription and longer term changes in the epigenetic status of promoters,” the authors wrote.
 
The researchers suggest that understanding this process could be particularly useful given the role of methylation in controlling some estrogen-related promoters and the established links between breast cancer and estrogen.
 
“In particular, breast cancer is affected by estrogen signaling and changes in epigenetic control,” co-senior author George Reid, a scientist at EMBL, said in a statement. “Our next step will be to find small molecules that target the cyclical methylation processes to elucidate their precise role.”

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