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Researchers map human genome in 4-D as it folds

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, is published in Cell.

Researchers map human genome in 4-D as it folds
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 [Credit: 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, forming loops along the chromosome. By rearranging these DNA elements in space, the cell is able to change which genes are active.

Close-up on a single extrusion complex in a computer simulation of DNA extrusion. First, an extrusion complex 
containing two subunits attaches to DNA, forming a small loop. Next, the two subunits slide along the DNA 
in opposite directions, while remaining physically tethered, growing the loop 
[Credit: Baylor College of Medicine]

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.

A simulation of DNA loops and domains forming through loop extrusion. In the extrusion model, an extrusion complex 
(yellow) containing two subunits first attaches to DNA, forming a small loop. Next, the two subunits slide along the 
DNA in opposite directions, growing the loop. The extrusion complex looks for a specific motif (purple triangles) 
which causes a protein called CTCF to bind to the DNA. If a subunit encounters a CTCF motif that is pointing at it, 
the subunit tends to stop. If the CTCF motif is pointing in the other direction, the motif won’t be recognized. 
A schematic of the extrusion process is shown below the simulation. Two domains are formed, shown 
in red and blue  [Credit: Baylor College of Medicine]

“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.”

Source: Baylor College of Medicine [October 05, 2017]

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