Epigenetics and methylation: New DNA bases linked to protein

Adenine, thymine, cytosine and guanine: These are the nucleobases, or just plain bases of DNA that in pairs called nucleotides carry the genetic code of life. There are four of them, right? At least that’s what most everybody learns. Of course, there is another base, uracil, which is found in RNA where it replaces thymine. But wait, there’s more. More bases that is, or at least that’s what biochemists call them, although their names are unfamiliar. In fact, now there are four of them: 5-methylcytosine (first discovered), 5-hydroxymethylcytosine, and most recently 5-formylcytosine and 5-carboxycytosine. These last two were finally reproduced in the laboratory by Yi Zhang and team at the University of North Carolina (USA) in Science Express [21 July 2011, paywalled, Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine].

It seems pretty obvious that these new bases 5 through 8 are not replacements for the more common four. So what’s the deal, why are these unmemorable variants of cytosine important?

They are the result of a process called methylation. In DNA methylation is a chemical process that adds an organic molecule, a methyl group with a basic formula of CH3, to the base cytosine. When a methyl group is tacked onto a nucleotide, it changes its characteristics, namely the configuration or shape. Simply put, it causes that portion of the double helix to fold into itself. This shields the underlying nucleotide from activation – in short, it’s turned off. Most of the human chromosome available for methylation has been turned off in this way. Where they are not turned off, that’s where a very large percentage of genes are ‘expressed’ – involved in producing protein.

What genetic scientists are discovering is that while DNA may provide the blueprint or basic instructions for building proteins, which genes are involved at what specific time and in what specific ways is often the result of the process of methylation. Methylation is how living cells respond to the environment. For example, a response to stress conditions is represented by changing patterns of methylation, turning genes on and off. These changes are then copied when new cells are made. It’s a process studied as the relatively new field of epigenetics.

What the Zhang team discovered is that a particular protein group called Tet is responsible for the conversion of cytosine in a nucleotide into 5-methylcytosine and then the other three methylated bases. While the details of how this works are still part of the ongoing research, it seems likely that the interaction of Tet proteins with DNA is a key element in the methylation process.

This makes the Tet proteins a potentially important subject for genetic and medical research. Someday, though not soon, the process of methylation through Tet proteins will be better understood. It may be possible to use Tet protein in some form to control the methylation of genes (turning them on or off). It would be hard to overestimate how powerful (and dangerous) a tool this might be, for it could be a pathway to controlling epigenetics. This could include countering the environmental causes of cancer or reprogram adult cells into stem cells.

That potential is still far away, but with this advance in the understanding of DNA methylation scientists move closer to understanding the mechanics of epigenetics.

[SciTechStory: Part of what makes us human may be what’s missing]
[SciTechStory: Small steps toward understanding the epigenome]

Research Spectrum

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