Check Up: In the loop on gene activation

Posted: February 19, 2013

Human genes seem to be activated by stretches of DNA found in between the genes but not very close to them. Each activator is often located thousands of base pairs away from its corresponding gene, so scientists have been puzzled as to just how they get the job done.

Researchers at Wistar Institute reported on Sunday that they had found part of the answer: At the appropriate moment, each gene and its activator come together as if the DNA were string being tied into a loop.

The findings help to explain what occurs during embryonic development, when the pinpoint timing of gene activation plays a role in whether a cell becomes part of, say, a liver or a heart, and even whether the organism is a human or another species.

The work, reported online in the journal Nature, was led by biochemist Ramin Shiekhattar, a professor at the 120-year-old research center in West Philadelphia.

The activators fall within the realm of what used to be called "junk DNA," but that term fell out of favor years ago as scientists learned of its important role. Shiekhattar prefers to call it "dark matter," borrowing an astronomy term for a phenomenon that is similarly mysterious yet clearly important.

"We're revealing a possible role for this dark matter of biology," Shiekhattar said.

The segments of DNA that activate genes contain the recipe for DNA's genetic cousin, RNA. But these RNAs are not the kind you learned about in high school biology - the messengers that ferry genetic code to the protein-making machines called ribosomes. They are noncoding RNAs, and they seem to activate neighboring genes by working in concert with a protein complex that scientists have nicknamed "mediator."

The activation process, with the distant portions of DNA coming together in a loop through some kind of chemical interaction, is not something that can be seen with a camera. Instead, Shiekhattar and his colleagues mapped out the process with a technique called chromosome conformation capture, which relies on chemical probes to tease out the configuration of genetic material.

And voilĂ , they could "see" the loop.

"You basically form a loop bringing these two sites in close proximity to each other," Shiekhattar said.

The researchers demonstrated that the noncoding RNA was vital to the looping process by showing that it did not work if they depleted the RNA in cell culture.

Shiekhattar was joined in the research by Wistar colleagues Fan Lai and Matteo Cesaroni and by coauthors from several other institutions, including Children's Hospital of Philadelphia.

Shiekhattar predicts the knowledge will prove useful not just in studying embryonic development, but also in cancer, a disease in which genetic activation runs amok.

- Tom Avril

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