First 4D map of human genome folding created

Scientists, including one of Indian origin, have created the first high-resolution four- dimensional (4D) map of human gene folding, tracking an entire genome as it folds over time. The advance by researchers, including those from Stanford University and Harvard University in the US, may lead to new ways of understanding genetic diseases. 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. However, 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 is hard to figure out how things work," said Suhas Rao, a medical student at Stanford University. "Our current approach is more like making a movie; we can watch folds as they disappear and reappear," said Rao, first author of the study published in the journal Cell.

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. "Extrusion works like the strap-length adjustor on a backpack," said Erez Lieberman Aiden, director of the Center for Genome Architecture at Baylor College of Medicine in the US.

"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 adjustor," said Aiden. 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. "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," he said.