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DNA origami: The linear sequence of a segment of chromosome 14 has been folded in a fractal folding pattern using origami, the Japanese art of paper folding. Researchers believe that DNA employs a three-dimensional fractal folding pattern inside the cell nucleus.

Using this new technology, the researchers identified two organizing principles in DNA. Chromosomes appear to be folded in such a way that active genes–those that are being made into proteins–are close together, and inactive genes are also close together, properties that had previously only been observed on a smaller scale. “The active stuff tends to be in one compartment that is not so densely packed,” says Lieberman. “The second compartment is like a storage compartment–it’s a bit denser and holds most of the genome.” Adds Dekker: “We think this is an efficient way for cells to organize chromatin within the nucleus.”

The researchers also developed a model for how they think DNA is organized within these active and inactive compartments. DNA molecules appear to form a polymer structure known as a fractal globule, in which segments that are close to each other in the linear sequence are also close in the three-dimensional globule. Lieberman likens the structure to a fresh packet of ramen noodles, before they are stirred into a tangled glob. “It suggests there is a kind of beautiful un-entangled structure that the genome folds into,” says Lieberman. “It has no knots, and a very simple physical process can be used to pull out a piece of fractal globule and then put it back.”

The technology makes it possible to tackle a number of questions, such as how the three-dimensional structure of the genome varies among cell types, among organisms, and between normal and cancerous cells. “Maybe this could help explain why cancer genomes are so misregulated,” says Dekker.

But it’s not yet clear how quickly the technology will catch on. While fast, cheap sequencing has made such experiments possible, “it is still a major undertaking,” says Misteli. That may change as prices continue to fall.

The researchers now hope to improve the resolution of the technology. Currently, they can examine the three-dimensional structure of the genome on a megabase scale–in units of a million DNA letters–but they are ultimately aiming for a kilobase resolution. “I think there are more structural features we haven’t discovered,” says Dekker. Increasing the resolution by a factor of 10 will require a hundredfold more sequencing, he says.

Scientists also want to explore exactly how the three-dimensional structure of the genome affects regulation. “What happens when you move a gene artificially from an inactive to an active area?” asks Dekker. “People have started to develop methods to move genes around in the nucleus, but the results are generally mixed.”

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Credits: Leonid A. Mirny and Maxim Imakaev, Designed and folded by Jason Ku. Photo by Erik Demaine. Thanks to Brian Chan, Erik Demaine, Martin Demaine, and Erez Lieberman-Aiden.

Tagged: Biomedicine, DNA, genome, human genome, origami

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