Gene On-off Switch Works Like Backpack Strap

Texas Medical Center-based team unravels how loops form in genome

Jo-Carolyn Goode | 10/19/2015, 3:28 p.m.
A research team based in Houston's Texas Medical Center has found that the proteins that turn genes on by forming ...
Erez Lieberman Aiden A. Sanchez/Baylor College of Medicine

The protein complex that forms DNA loops takes up slack by feeding DNA through from either direction until it hits the DNA keyword, or motif, which acts like a brake. The motifs must point in the correct direction; if they point away from the protein complex, it will not recognize them and will keep taking up slack.

A. Sanborn, S. Rao

The protein complex that forms DNA loops takes up slack by feeding DNA through from either direction until it hits the DNA keyword, or motif, which acts like a brake. The motifs must point in the correct direction; if they point away from the protein complex, it will not recognize them and will keep taking up slack.

HOUSTON – (Oct. 19, 2015) – A research team based in Houston's Texas Medical Center has found that the proteins that turn genes on by forming loops in human chromosomes work like the sliding plastic adjusters on a grade-schooler's backpack. This discovery could provide new clues about genetic diseases and allow researchers to reprogram cells by directly modifying the loops in genomes.

The study, which appears online this week in the Proceedings of the National Academy of Sciences, is by the same team that published the first high-resolution 3-D maps showing how the human genome folds inside the nucleus of a cell. The multi-institutional group includes researchers from Baylor College of Medicine, Rice University, Stanford University and the Broad Institute.

Every human cell contains a genome, a linear string of DNA. Sequences of DNA bases spell out genes, much like letters spell out words. For decades, scientists have known that genes that lie far apart on the string can activate one another by looping back and coming into contact during genome folding. Last year, the team showed that it was possible to map the positions of these loops, and the researchers created the first atlas of loops in the human genome. But the group couldn’t explain how the loops were forming.

"For months, we had no idea what our data really meant," said senior author Erez Lieberman Aiden, a geneticist and computer scientist with joint appointments at Baylor and Rice. "Then one day, we realized that we'd been carrying the solution around -- literally, on our back -- for decades!"

The human genome contains more than 20,000 genes. In any given cell, only a fraction of these are active, and this fraction determines the cell's function: whether it will become a hard-pumping heart cell, a body-defending immune cell or a metastatic cancer cell. Many genes are activated by loops, and it is impossible to understand gene activation without knowing how loops form, Aiden said.

Aiden, who is also a senior investigator at Rice's Center for Theoretical Biological Physics, said the researchers found that a set of proteins acts like the plastic slider, sometimes called a tri-glide, that adjusts a backpack strap.

"The mechanism that makes this possible can be explained to any kindergartener with a backpack," said study co-first author Adrian Sanborn, a graduate student in the Aiden lab and at Stanford University. "The protein complex that forms DNA loops appears to operate like the plastic slider that is used to adjust the length of the straps: it lands on DNA and takes up slack to form a loop."

Aiden, assistant professor of genetics at Baylor and of computer science and computational and applied mathematics at Rice, said Sanborn and study co-first author Suhas Rao showed that they could combine the tri-glide model with mathematics and high-performance computation to predict how a genome will fold. The team confirmed their predictions by making tiny modifications in a cell's genome and showing that the mutations changed the folding pattern exactly as expected. Rao likened the result to a new form of genome surgery: a procedure that can modify how a genome is folded by design and with extraordinary precision.