Research News
Unlocking the Mysteries of How Genomes Fold
Using a novel method that combines massively parallel genome sequencing with a chemical technique that links DNA sequences sitting next to each other in space, a team of investigators headed by Job Dekker, Ph.D., of the University of Massachusetts Medical School, and Eric Lander, Ph.D., of the Broad Institute, has deciphered the three-dimensional structure of the human genome. The results of this study open new avenues to understanding gene function and provide key insights into how cellular DNA folds at scales that dwarf the double helix.
The researchers, writing in the journal Science, report two striking findings. First, the human genome is organized into two separate compartments, keeping active genes separate and accessible while sequestering unused DNA in a denser storage compartment. Chromosomes snake in and out of the two compartments repeatedly as their DNA alternates between active, gene-rich and inactive, gene-poor stretches. “Cells cleverly separate the most active genes into their own special neighborhood, to make it easier for proteins and other regulators to reach them,” says Dekker.
Second, at a finer scale, the genome adopts an unusual organization known in mathematics as a "fractal." The specific architecture the scientists found, called a "fractal globule," enables the cell to pack DNA incredibly tightly -- the information density in the nucleus is trillions of times higher than on a computer chip -- while avoiding the knots and tangles that might interfere with the cell's ability to read its own genome. Moreover, the DNA can easily unfold and refold during gene activation, gene repression, and cell replication. "Nature's devised a stunningly elegant solution to storing information -- a super-dense, knot-free structure," says Lander.
Prior to this study, many scientists had thought that DNA was compressed into a different architecture called an "equilibrium globule," a configuration that is problematic because it can become densely knotted. The fractal globule architecture, while proposed as a theoretical possibility more than 20 years ago, has never previously been observed.
Key to the current work was the development of the new Hi-C technique, which permits genome-wide analysis of the proximity of individual genes. The scientists first used formaldehyde to link together DNA strands that are nearby in the cell's nucleus. They then determined the identity of the neighboring segments by shredding the DNA into many tiny pieces, attaching the linked DNA into small loops, and performing massively parallel DNA sequencing. By breaking the genome into millions of pieces, the investigators were able to create a spatial map showing how close different parts are to one another.
The details of this study appear in a paper titled, “Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome.” An abstract of this paper is available at the journal’s Web site.
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