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, tracking 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.
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, forming loops along the chromosome. By rearranging 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, without the ability to 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.
“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 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.”
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, Hertz Fellow and a senior investigator at Rice University’s Center for Theoretical Biological Physics. “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,” explained Rao. “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.”
Other contributors to the work include Su-Chen Huang, Brian Glenn St. Hilaire, Jesse Engreitz, Elizabeth Perez, Kyong-Rim Kieffer-Kwon, Adrian Sanborn, Sarah Johnstone, Gavin Boscom, Ivan Bochkov, Xingfan Huang, Muhammad Shamim, Jaewon Shin, Douglass Turner, Ziyi Ye, Arina Omer, James Robinson, Tamar Schlick, Bradley Bernstein and Rafael Casellas. Aiden is also a member of the Dan L Duncan Comprehensive Cancer Center at Baylor.
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, an NIGMS award, an NIH New Innovator Award, an NSF Physics Frontier Center grant, the NHGRI Center for Excellence for Genomic Sciences, the Welch Foundation, and NVIDIA Research Center Award, an IBM University Challenge Award, a Google Research Award, a Cancer Prevention 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.