By Allison Proffitt
October 8, 2009 | Using a new technique, researchers revealed the first complete view of the 3-D structure of the genome and the way chromosomes arrange themselves in the nucleus. The work was done by scientists at Harvard University, the Broad Institute of Harvard and MIT, University of Massachusetts Medical School, and the Massachusetts Institute of Technology, and published in Science.
The technology, explains Job Dekker, associate professor of biochemistry and molecular pharmacology at UMass Medical School and a senior author of the paper, was built on an existing technology that had previously been applied to only two loci, but in this case was applied to the whole genome.
Co-first author Nynke van Berkum, a postdoctoral researcher at UMass Medical School in Dekker's laboratory, explains the process. “We grow cells and we crosslink the cells using formaldehyde so chromatin that are close to each other link, then we fragment the DNA… What happens is you get these molecules in your solution that are crosslinked to each other representing two fragments that were originally close to each other in the nucleus.”
The team used Illumina paired end sequencing to reconstruct the genome from these neighboring fragments and determine the original shape. “This generates an enormous dataset that tells us what the neighbors are at any different loci,” says Dekker. “No optical methods were used to look at the chromosomes.”
Co-first author Erez Lieberman-Aiden, a graduate student in the Harvard-MIT Division of Health Science and Technology and a researcher at Harvard's School of Engineering and Applied Sciences and in the laboratory of Eric Lander at the Broad Institute, lead the computational efforts.
“A long standing question has been how do you fit such a long genome in a tiny nucleus in a way that’s still functional? How do you solve that problem so that it’s biologically active?” Dekker tells Bio-IT World, and he calls the findings “very surprising and very different from what people have thought before.”
The results of the new technology showed that active and gene-rich portions of chromosomes are segregated from inactive portions. “One compartment has all the active stuff and the other compartment has the inactive stuff. The cell can focus on the active parts while ignoring the inactive parts,” says Dekker.
Within the two compartments, the chromosomes aren’t a tangled, knotted mess, but organized in a way Dekker calls, “very dense but very efficient… It’s a really beneficial way of packing. If you want to unfold a little section that you want to access, you can effectively just unfold that section. Very convenient.”
“The technique allows us to look at the whole genome all at once,” says van Berkum. “It’s a huge improvement to anything that’s around at this point. Looking at the whole genome and looking at different processes like differentiation of cells, cells in the cell cycle, now that we can see the whole genome at once we can see what’s really happening.”
Dekker was equally enthusiastic about the future applications of the work and believes it will shift genome research from a linear approach—simply reading genetic code—to a spatial approach considering genes’ proximities to each other and locations in the genome as a whole, an approach he believes will inform gene regulation. “I suspect in the next one or two years we’ll be able to get much higher resolution pictures of whole genomes and its going to help us understand better how genomes function.”