Scientists have discovered proteins that switch on genes by forming loops in human chromosomes operate in a similar fashion to the sliding plastic adjusters on a grade-schooler's backpack.
This new evidence could provide insight into genetic diseases and even lead to a way for scientists to reprogram cells by modifying the loops in the genome, Rice University reported. Last year the researchers made the discovery that they could map the genome loops, and created the first "atlas" of the phenomenon.
"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!"
Many genes are activated by loops, but in order to understand how this gene activation worked researchers first had to uncover how they form. The researchers found a set of proteins that act like a plastic slider (tri-glide) on backpack straps. The researchers confirmed their results by making tiny modifications in a cell's genome and demonstrating the mutations changed the folding pattern in the exact way they had expected.
"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."
This new knowledge allowed the researchers to come up with a new way to combine the tri-glide model with mathematics and high-performance computation to predict how a genome will fold. The findings could lead to a new form of genome "surgery" that modifies how a gene is folded with incredible precision.
"We found that changing even one letter in the genetic code was enough to modify the folding of millions of other letters," said study co-first author Suhas Rao. "What was stunning was that once we understood how the loops were forming, the results of these changes became extremely predictable."
The findings were published in a recent edition of the journal Proceedings of the National Academy of Sciences.
