Researchers map human genome in 4-D as it folds

Time-lapse view reveals new mechanism that brings DNA elements together

By Allison Mickey
Special to the Rice News

A multi-institutional team spanning Baylor College of Medicine, Rice University, Stanford University and the Broad Institute of MIT and Harvard has created the first high-resolution 4-D map of genome folding, which tracks an entire human genome as it folds over time. The report, which may lead to new ways of understanding genetic diseases, appears on the cover of Cell.

An artist’s interpretation of chromatin folded up inside the nucleus. The artist has rendered an extraordinarly long contour into a small area, in two dimensions, by hand. (Image by Mary Ellen Scherl)

Making connections

For decades, researchers have suspected that when a human cell responds to a stimulus, DNA elements that lie far apart in the genome quickly find one another and form loops between elements that are far apart along the chromosome. By re-arranging these DNA elements in space, the cell is able to change which genes are active.

In 2014, the same team of scientists showed it was possible to map these loops. But the first maps were static; the researchers could not watch the loops change. It was unclear whether, in the crowded space of the nucleus, DNA elements could find each other fast enough to control cellular responses.

Suhas Rao (A. Sanchez/Baylor College of Medicine)

“Before, we could make maps of how the genome folded when it was in a particular state, but the problem with a static picture is that if nothing ever changes, it’s hard to figure out how things work,” said Stanford medical student Suhas Rao, first author of the new study. “Our current approach is more like making a movie: We can watch folds as they disappear and reappear.”

One ring to rule them all

To track the folding process over time, the research team began by disrupting cohesin, a ring-shaped protein complex that was located at the boundaries of nearly all known loops. In 2015, the team proposed that cohesin creates DNA loops in the cell nucleus by a process of extrusion.

Erez Lieberman Aiden. Credit: A. Sanchez/Baylor College of Medicine

“Extrusion works like the strap-length adjuster on a backpack,” said Erez Lieberman Aiden, director of Baylor’s Center for Genome Architecture, a senior investigator at Rice University’s Center for Theoretical Biological Physics and senior author on the new study. “When you feed the strap through either side, it forms a loop. DNA seems to be doing the same thing — except that cohesin rings appear to play the role of the adjuster.”

Aiden said a crucial prediction of the 2015 model is that all the loops should disappear in the absence of cohesin. In the new research, Aiden, Rao and colleagues tested that assumption.

“We found that when we disrupted cohesin, thousands of loops disappeared,” said Rao, a member of the Aiden lab. “Then, when we put cohesin back, all those loops came back — often in a matter of minutes. This is precisely what you would predict from the extrusion model, and it suggests that the speed at which cohesin moves along DNA is among the fastest for any known human protein.”

Loops versus groups

But not everything happened as the researchers expected. In some cases, loops did the exact opposite of what the researchers anticipated.

“As we watched thousands of loops across the genome get weaker, we noticed a funny pattern,” said Aiden, also a McNair Scholar at Baylor. “There were a few odd loops that were actually becoming stronger. Then, as we put cohesin back, most loops recovered fully — but these odd loops again did the opposite — they disappeared!”

By scrutinizing how the maps changed over time, the team realized that extrusion was not the only mechanism bringing DNA elements together. A second mechanism, called compartmentalization, did not involve cohesin.

“The second mechanism we observed is quite different from extrusion,” Rao said. “Extrusion tends to bring DNA elements together two at a time, and only if they lie on the same chromosome. This other mechanism can connect big groups of elements to one another, even if they lie on different chromosomes. And it seems to be just as fast as extrusion.”

Broad Institute Director Eric Lander, a study co-author, said, “We’re beginning to understand the rules by which DNA elements come together in the nucleus. Now that we can track the elements as they move over time, the underlying mechanisms are starting to become clearer.”

For a list of other contributors to the work, click here.

This project was supported by a Paul and Daisy Soros Fellowship, a Fannie and John Hertz Foundation Fellowship, a Cornelia de Lange Syndrome Foundation grant, a Stanford Medical Scholars Fellowship, a National Institute of General Medical Sciences award, a National Institutes of Health (NIH) New Innovator Award, a National Science Foundation Physics Frontier Center grant, the National Human Genome Research Institute’s Center for Excellence for Genomic Sciences, the Welch Foundation, an NVIDIA Research Center Award, an IBM University Challenge Award, a Google Research Award, a Cancer Prevention and Research Institute of Texas Scholar Award, a McNair Medical Institute Scholar Award, an NIH 4-D Nucleome Grant, an NIH Encyclopedia of DNA Elements Mapping Center Award and the President’s Early Career Award in Science and Engineering.

–Allison Mickey is a senior communications specialist at Baylor College of Medicine.