News Release: Research , School of Medicine

Jun. 24,  2011

Patterns in embryonic cells give hints to function of DNA's "sixth letter"

News Article ImageThe distribution of 5-hmC (green) differs from that of 5-mC (red), especially at the centers of chromosomes (arrows).

Imagine arriving in a country where you did not know the language at all. You’d have to guess the meaning of street signs based on context. This process of deciphering is similar to what scientists are doing with a recently discovered “sixth nucleotide.”

Researchers at Emory University School of Medicine have mapped the distribution of 5-hydroxymethylcytosine (5-hmC) in human embryonic stem cells, comparing it with the distribution of regulatory proteins known to be important in stem cell maintenance.

The results were published online this week by the journal PLoS Genetics. It is the first report on 5-hmC in human embryonic stem cells. The senior author is Peng Jin, PhD, associate professor of human genetics at Emory University School of Medicine, with postdoctoral fellow Keith Szulwach as first author. Collaborators included Young-sup Yoon, MD, PhD, associate professor of medicine (cardiology) at Emory and investigators from UCSD and University of Chicago.

The Emory team used a method they developed in cooperation with scientists at the University of Chicago to chemically label 5-hmC. Previously, chemical techniques did not allow scientists to tell the difference between 5-hmC and 5-methylcytosine (5-mC).

Both are punctuation-like modifications of cytosine, one of the four bases that make up DNA. Like a colon and a semicolon, 5-mC and 5-hmC look very similar, but their meanings and contexts are different.5-mC and 5-hmC look very similar, but their functions appear to diverge.

5-mC has been well-studied and is generally found on genes that are turned off. When stem cells change into the cells that make up skin, blood, muscle or brain, 5-mC helps shut inappropriate genes off. Changes in its distribution also underpin a healthy cell’s transformation into a cancer cell.

In contrast to 5-mC, 5-hmC appears to be enriched on active genes, especially in brain cells. This is a puzzle for biologists, because the two kinds of DNA modification are so closely related.

It looks like 5-hmC can only appear on DNA where 5-mC already was. Adding a 5-hmC could be the beginning of a process to remove a 5-mC mark, except that there are hints that it could have its own special function. The 5-hmC distribution pattern seen in embryonic stem cells is different from that in the brain, the researchers found.

“5-hydroxymethylcytosine appears to be important for maintaining stem cell potential,” Jin says. “At the same time, it also seems to have a role in silencing the genes that would be activated if stem cells were to differentiate into various tissues. What we see suggests that 5-hmC tempers the activity of some genes, maintaining their potential to be more fully expressed when needed.”

5-hmC is enriched on some promoters and enhancers, regions of DNA that act as control buttons, determining whether a nearby gene or genes are turned on or off. In addition, 5-hmC is enriched along the same parts of the genome as Nanog, a protein that is critical for stem cells’ ability to renew themselves and generate many types of tissues.

The research was supported by the National Institutes of Health.

Reference: K.E. Szulwach et al. Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genetics (2011).

Writer: Quinn Eastman

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The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service.

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