New Technology Reveals the Genome’s 3D Shape

Hi-C technique looks at chromosomes at unprecedented level of resolution

Try taking a human hair as long as Manhattan and cramming it—unsnarled—inside a marble. This is the challenge faced by a 2-meter-long strand of DNA as it folds into its compact array of 23 chromosomes within a cell’s nucleus. Previously, scientists only theorized about how DNA squeezes inside a nucleus without becoming a hopelessly tangled mass. Now a new technique called Hi-C reveals that DNA packs knot-free into its chromosomal patterns by assuming a rare geometric shape observed in snowflakes, crystals and broccoli.

 

In the fractal globule (above left), nearby regions on a chain of DNA—indicated using similar colors—are packed into nearby regions in 3D space. The accessible DNA chain unravels easily (above right) because the globule lacks knots. Images courtesy of Leonid A. Mirny and Maxim Imakaev, reprinted from Lieberman-Aiden, E., et al., Comprehensive Mapping of Long-Range Interactions Reveal Folding Principles of the Human Genome, Science, 326(5950): 289-293 (2009), with permission from AAAS.“We’ve developed a powerful new technique to look at chromosomes at an unprecedented resolution,” says Job Dekker, PhD, cell biologist at the University of Massachusetts and coauthor of the study in the October 9, 2009 issue of Science. “What we found constitutes a breakthrough in our understanding of chromosome folding.”

 

At the small scale, DNA wraps around proteins called histones and assumes its classical double-helix shape. At the large scale, chromosomes cluster in discrete sections within the nucleus called “territories.” “Between the scale of chromosome territories and the scale of histones, effectively nothing has been known about the structure of the genome,” says first author Erez Lieberman-Aiden, a graduate student in the lab of Eric Lander, PhD, professor of biology at the Broad Institute in Cambridge, Massachusetts.

 

Hi-C reconstructs an unbiased 3-D map of the entire genome. First, scientists soak a complete set of chromosomes in formaldehyde, which acts like glue to stick together parts of the genome that are close in 3-D space. Then they chop the DNA into a million pieces and perform massive parallel sequencing on the interacting fragments. Mapping software compares the sequences of attached fragments with a human genome reference sequence; based on the results, the scientists compute which parts of the folded DNA physically interact with each other.

 

The team found that active, gene-rich and inactive, gene-poor sections cluster in separate parts of the nucleus. The active chromatin segments are like easily accessible papers spread out across a desk, whereas the inactive portions are densely packed, like folders in a file cabinet.

 

Simulations revealed that DNA assembles into dense fractal globules—structures that look alike at different levels of magnification, such as the intricate geometrical form of a crystal. Genes are easily accessible, but when they’re not in use, the structure spontaneously collapses into a tight, knot-free bundle.

 

“This is the first spatial map of the genome,” says Tom Misteli, PhD, cell biologist at the National Cancer Institute in Bethesda, Maryland. “It’s a technical breakthrough that opens the doors to doing all sorts of interesting experiments.”

 

Future experiments will investigate how the 3-D shape of DNA morphs depending on the activity of genes and disease states, like cancer. As genome sequencing becomes cheaper, Dekker says, it should be possible to obtain higher spatial resolution and even to reconstruct the shapes of individual genes.



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