Next time you pull your iPod out of your bag and begin untangling the headphone cord, think about this: that cord is one third the length of the human genome. And those headphones are compressed into a bag that is incomparably larger than a nucleus. “It takes me a long time to untangle that cord,” said co–first author Erez Lieberman-Aiden, a graduate student in the Harvard–MIT Division of Health Sciences and Technology.
Yet in a cell, the genetic instructions crammed inside the nucleus must always be available. So how do chromosomes pack themselves into this tiny space and still remain accessible?
For years, scientists thought that chromosomes fold into a shape called an “equilibrium globule.” But this shape “is effectively a massive, massive Gordian knot,” said Lieberman-Aiden. “It’s a lousy model” for genome folding.
In new work that both extends mathematical theory and introduces new 3-D genome mapping technology, Lieberman-Aiden and colleagues discovered a new shape. Previous work showed that a polymer strand resembling DNA will, when placed in a solvent, form an equilibrium globule. But the team’s new experiments showed that it forms a tidier fractal globule first.
The fractal globule is just as dense as the equilibrium model, but it contains no knots. “You can pull out a piece, open it up, look at it, then push it back in,” said Lieberman-Aiden. “Everything we know about genome folding fits with this remarkable fractal model.”
The new model, described in the Oct. 9 Science, meets layers of complex cellular needs with a breathtaking elegance and simplicity; its fractal nature adds spatial organization and accessibility at many different scales.
“I think it proves once and again how efficiently nature is put together,” said co–first author Nynke van Berkum, a research fellow at the University of Massachusetts Medical School. “If you think it’s complicated, probably there is another solution. The equilibrium globule was very complicated. Now that we see the fractal globule and how it folds, we think: yes, it makes sense.”
Students may contact Eric Lander at eric@broad.mit.edu (website http://www.broadinstitute.org/about/bios/bio-lander.html) or Job Dekker at Job.Dekker@umassmed.edu (website http://www.umassmed.edu/pgfe/faculty/Dekker.cfm) for more information.
Conflict Disclosure: A provisional patent on the Hi-C three-dimensional genome mapping technology is under review.
Funding Sources: A Fannie and John Hertz Foundation fellowship, a National Defense Science and Engineering fellowship, an NSF fellowship, the National Space Biomedical Research Institute, the National Human Genome Research Institute, the National Institutes of Health, an American Society of Hematology fellowship, and the Keck Foundation; the authors are solely responsible for the content of this work.
