DNA's secret weapon against knots and tangles
A simple process seems to explain how massive genomes stay organized. But no one can agree on what powers it.
19 April 2017
Leonid Mirny swivels in his office chair and grabs the power cord for his laptop. He practically bounces in his seat as he threads the cable through his fingers, creating a doughnut-sized loop. “It's a dynamic process of motors constantly extruding loops!” says Mirny, a biophysicist here at the Massachusetts Institute of Technology in Cambridge.
Mirny's excitement isn't about keeping computer accessories orderly. Rather, he's talking about a central organizing principle of the genome — how roughly 2 metres of DNA can be squeezed into nearly every cell of the human body without getting tangled up like last year's Christmas lights.
He argues that DNA is constantly being slipped through ring-like motor proteins to make loops. This process, called loop extrusion, helps to keep local regions of DNA together, disentangling them from other parts of the genome and even giving shape and structure to the chromosomes.
Scientists have bandied about similar hypotheses for decades, but Mirny's model, and a similar one championed by Erez Lieberman Aiden, a geneticist at Baylor College of Medicine in Houston, Texas, add a new level of molecular detail at a time of explosive growth for research into the 3D structure of the genome. The models neatly explain the data flowing from high-profile projects on how different parts of the genome interact physically — which is why they've garnered so much attention.
But these simple explanations are not without controversy. Although it has become increasingly clear that genome looping regulates gene expression, possibly contributing to cell development and diseases such as cancer, the predictions of the models go beyond what anyone has ever seen experimentally.
For one thing, the identity of the molecular machine that forms the loops remains a mystery. If the leading protein candidate acted like a motor, as Mirny proposes, it would guzzle energy faster than it has ever been seen to do. “As a physicist friend of mine tells me, 'This is kind of the Higgs boson of your field',” says Mirny; it explains one of the deepest mysteries of genome biology, but could take years to prove.
And although Mirny's model is extremely similar to Lieberman Aiden's — and the differences esoteric — sorting out which is right is more than a matter of tying up loose ends. If Mirny is correct, “it's a complete revolution in DNA enzymology”, says Kim Nasmyth, a leading chromosome researcher at the University of Oxford, UK. What's actually powering the loop formation, he adds, “has got to be the biggest problem in genome biology right now”.
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