In a first, researchers have worked out a way to unravel and model the tangled, 3D structures of intact mammalian genomes from individual cells.

The new method, published Monday in Nature, could help researchers study how the complex loops, twists, and bunches of a tightly packaged genome influence which bits of the blueprints are actively used by the cells, and when.

In humans, for instance, genome packaging bundles nearly two meters’ worth of DNA strings into a nucleus about 0.005 millimeters wide. How all that DNA is bundled affects whether important genes are available for decoding by cellular machinery, while others are boxed up and shoved aside until they’re needed. Such carefully orchestrated genetic activity affects everything a cell does—from carrying out basic functions, to allowing stem cells to differentiate into any type of cell, to triggering diseases.

Tom Collins, a genetics and molecular scientist at Wellcome Trust, who was not a study author, called the new, more detailed method an exciting step forward. “This detail will reveal some of the underlying principles that govern the organization of our genomes—for example, how chromosomes interact or how structure can influence whether genes are switched on or off,” he said in a statement. “If we can apply this method to cells with abnormal genomes, such as cancer cells, we may be able to better understand what exactly goes wrong to cause disease and how we could develop solutions to correct this.”

To pull off the high resolution look at DNA-packaging, researchers at the University of Cambridge and the Wellcome Trust–MRC Stem Cell Institute joined colleagues to combine cell images and a molecular technique called Hi-C. First, the researchers took super zoomed-in images of eight mouse embryonic stem cells’ genomes. Next, researchers turned to Hi-C, an established method to reveal the structure of genome packaging based on DNA sequences that are caught residing near each other. (Hi-C isn’t an acronym. It’s a riff on 3C, a shorthand for Chromosome Conformation Capture Analysis.)

Basically, in Hi-C, the cells are fixed with formaldehyde so that bits of DNA held together by protein packing tape stay stuck together. Then researchers use enzymes that act like molecular scissors and snip the genome into tiny fragments. This leaves scraps of DNA strings held together by packaging proteins that are themselves held together by the formaldehyde.

Imagine two short pieces of DNA pinched together at the middle by a piece of tape, creating an X shape. Researchers then fuse those dangling DNA fragments together and create a single piece of DNA from the two fragments that were once just physically close together. After stripping away the tape, the researchers can sequence across the fusion points and reveal which bits of DNA were close to each other thanks to packaging.

From the eight stem cells, processed individually, the researchers captured between 37,000 and 122,000 DNA junctions. This represents just 1.2 to 4.1 percent of the total possible junctions that could have been in the genomes. But, combined with the high resolution images, they captured enough to assemble 3D structures. When the researchers overlaid data indicating which genes were active or dormant onto their 3D structures, that data squared with the genes’ positions within the messy balls.

"Knowing where all the genes and control elements are at a given moment will help us understand the molecular mechanisms that control and maintain their expression," said Ernest Laue, lead study author and biochemist at Cambridge.

Nature, 2017. DOI: 10.1038/nature21429 (About DOIs).