It’s a common storytelling trope: the stubborn foe who is eventually revealed to be a much-needed friend. 

Biology has its own version. Cornell researchers have discovered that DNA packaging structures called nucleosomes, which have been traditionally seen as roadblocks for gene expression, actually help reduce torsional stress in DNA strands and facilitate the decoding of genetic information.

“If gene expression does not proceed properly, it will lead to all kinds of problems. Abnormal cellular growth, cancer development and other disorders – they're all interconnected,” said Michelle Wang, the James Gilbert White Distinguished Professor of the Physical Sciences in the College of Arts and Sciences, who led the project. “Gene expression is at the heart of the central dogma of biology, and how that’s regulated dictates everything that’s coming downstream. I think we’re filling in a piece of the puzzle for something really fundamental that affects so many things.”

The findings were published Dec. 18 in Science. The lead author is postdoctoral researcher Jin Qian, Ph.D. ’23.

Transcription – a crucial step of gene expression – is a knotty process with a lot of moving parts, all of which are essential for any kind of cellular function. That’s because DNA essentially serves as the instruction manual for genes, and that information must be decoded, copied and then disseminated via RNA. 

But there’s a twist. DNA’s helical structure creates a problem similar to what happens when you try to unwind a tightly coiled rope: the more you unwind one section, the tighter the rest becomes. That’s what happens during transcription, as the motor enzyme RNA polymerase twists the DNA and slowly moves along it, copying the code. It’s not a smooth journey. The polymerase’s progression is hindered by nucleosomes, the basic packing units of DNA that make up chromatin. Not only must the polymerase overcome these obstacles, it must also rotate to track the DNA helix. These rotations supercoil the DNA and generate torsional stress, which acts as another obstacle. Yet somehow the process succeeds.

Wang’s lab has spent decades trying to pry open and understand the mechanics of such interactions. To do so, they needed to develop the right tools. Earlier, they invented the angular optical trap, which captures a nanofabricated quartz cylinder, allowing the researchers to grip one end of a DNA strand and twist it. They then built magnetic tweezers, which employ magnetic fields for a similar purpose.

The combination of those tools and years of foundational research enabled the team to stretch and supercoil DNA and measure torque and angular orientation on a molecular scale.

The long years of experimentation have clarified the role of nucleosomes during transcription. Crucially, nucleosomes wrap DNA in a left-handed direction – like a spiral staircase. This matters because DNA’s double helix naturally twists to the right.

The team’s most recent experiments show that these opposing chiralities actually work together to relieve the torsional stress that builds up during transcription. The polymerase gets additional assistance from topoisomerases, which act like molecular scissors: They make temporary cuts in the DNA to release torsion and then quickly seal the breaks back up.

“As polymerase moves forward, the chromatin becomes a torsional buffer. It releases that stress to allow transcription to move forward. We are really excited by this discovery,” Wang said. 

The finding demonstrates how complex biological functions can emerge from the simple physical properties of biomolecules, according to Wang, reappointed in 2025 as a Howard Hughes Medical Institute Investigator, an honor she was first awarded in 2008. Wang hopes that this support continues to drive more discoveries that will expand our understanding of fundamental processes like DNA transcription and replication. 

“We can take this in so many directions, things like nucleosome modifications and remodeling that could change chromatin mechanical properties, which then change how polymerase can go through a nucleosome,” Wang said. “There’s so many questions we can ask about gene expression. This is just the beginning.” 

Co-authors include former postdoctoral researchers Shuming Zhang and Chuang Tan; postdoctoral researcher Xiaomeng Jia; doctoral students Yifeng Hong and Taryn Kay; senior lecturer Robert Fulbright; research specialist James Inman; professor James Berger and his lab members Joshua Jeong and Glenn Hauk of Johns Hopkins University School of Medicine; and senior investigator Mikhail Kashlev and his associates Lucyna Lubkowska and Deanna Gotte of the National Cancer Institute.

The research was supported by the Howard Hughes Medical Institute and the National Institutes of Health.