Once upon a time, researchers knew that DNA contained four nucleotides: A, T, C and G. Then they found a fifth. And now they've found a sixth.

Called 5-hydroxymethylcytosine, it's a form of the fifth nucleotide, technically known as 5-methylcytosine. Like its forerunner, it helps turn genes on and off, but in ways that researchers didn't expect.

"I think this finding will electrify the field of epigenetics," said Nathaniel Heintz, a Rockefeller University molecular biologist, in a press release accompanying the findings, published Thursday in Science.

Epigenetics, or the study of gene activation, has blossomed since the Human Genome Project's completion in 2004. Controlled by a secondary layer of biochemical information — "epi" means "outside" — genes are turned on and off at different times and places in the body. That helps explain why, despite considerable genetic overlap, species take such different forms. (Humans and chimpanzees famously share 96 percent of their DNA.)

One powerful epigenetic mechanism is methylation, in which 5-methylcytosine replaces cytosine — the letter C — in a gene, telling the cellular machinery that turns genetic code into proteins to leave it unread. Heintz made his findings almost accidentally while developing new methods for studying methylation in mouse neurons.

According to Heintz, methylation performed by 5-hydroxymethylcytosine doesn't behave in the same way as that produced by old-fashioned 5-methylcytosine. And just to make the situation trickier, standard methods of methylation detection can't distinguish between the two forms.

Further research is needed to show if the new methylation method is present in humans, but it may be. An accompanying Science paper by researchers from Harvard University and the National Institutes of Health describes the detection in humans of 5-hydroxymethylcytosine-producing enzymes.

Time will tell whether Heintz' prediction was skewed by the giddiness of discovery, but the findings are intriguing. If 5-hydroxymethylcytosine is as unique and important as he says it is, new epigenetic measurement tools will need to be developed. The Human Epigenome Project may need to be recalibrated.

See Also:

*Citations: "Conversion of 5-Methylcytosine to

5-Hydroxymethylcytosine in Mammalian DNA by the MLL Fusion Partner

TET1." By Mamta Tahiliani, Kian Peng Koh, Yinghua Shen, William A.

Pastor, Hozefa Bandukwala, Yevgeny Brudno, Suneet Agarwal,

Lakshminarayan M. Iyer, David R. Liu, L. Aravind, Anjana Rao. Science,

Vol. 324 Issue 5925, April 17, 2009. *

"The Nuclear DNA Base

5-Hydroxymethylcytosine Is Present in the Brain and More Abundant in

Purkinje Neurons." By Skirmantas Kriaucionis and Nathaniel Heintz.

Science, Vol. 324 Issue 5925, April 17, 2009.

Image: Science

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