19 March 2006

DNA Methylation: Reversible Gene Expression in Cancer and Development

DNA methylation is one way that gene expression is controlled. In a previous post I discussed the use of hypomethylating drugs to de-methylate tumor suppressor genes, thus reactivating them, as a good way to treat cancer.

DNA methylation is involved from the very beginning of human embryonic development. In early development (fertilisation to 8-cell stage), the eukaryotic genome is demethylated. From the 8-cell stage to the morula, de novo methylation of the genome occurs, modifying and adding epigenetic information to the genome. By blastula stage, the methylation is complete. This process is referred to as "epigenetic reprogramming".

This newsrelease discusses new findings in DNA methylation--how methylation can be thought of more as a dimmer switch, and less as an on-off switch.

A gene is like a long sentence that describes the structure of a protein. The letters in the sentence are spelled out in the building blocks of the DNA strand of which the gene is part.

Like a sentence, a gene has a well-defined starting point, called the start site. Unlike a sentence, a gene has a second region that runs to the left of the start site. That region is known as the promoter, and this is the off-and-on switch for the gene.

DNA methylation involves chemical changes that take place in the promoter region. These changes alter the gene so that it cannot be turned on. Usually, these chemical changes occur in areas of the promoter that are close to the start site, and that’s where others have looked for them in the C/EBPa gene.

Plass and his colleagues, however, looked two to three times farther from the start site than usual.

“We were surprised to find that methylation had occurred along this region far upstream from the start site,” Plass says.

DNA methylation is very complex, and central to both animal development, and gene expression of the mature animal. Methylation can shut down oncogenes--preventing cancer--and methylation can shut down tumor suppressor genes--allowing cancer to progress. The B-vitamin Folic Acid is intimately involved in DNA methylation, and this article provides useful background to the critical role of folate in both preventing and promoting cancers.

DNA methylation falls into the category of epigenetics. Epigenetic regulation of gene expression can largely determine the difference between a chimpanzee and a human.

Perhaps mastering epigenetics will reduce the need for vectored gene therapy, at least in the short run.

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