Back-to-back Nature papers reveal RNA-guided CRISPR system that activates gene expression

03-24-2026

In back-to-back studies published in Nature, researchers from Purdue University and Columbia University report a naturally evolved gene-editing system that can activate genes, offering an advantage over existing CRISPR gene-editing systems that merely find and cut DNA. The research includes two complementary studies, one examining the biological function of the system and the other revealing the molecular mechanism that enables it.

The team’s research on a variant of the CRISPR — Clustered Regularly Interspaced Short Palindromic Repeats — system broadens understanding of CRISPR’s natural diversity and provides a foundation for new gene-regulation technologies. Because this CRISPR variant activates genes without cutting DNA, it could be adapted for precise gene control applications, including research tools and potential therapeutic strategies that turn on genes without permanently altering the genome.

“In traditional CRISPR, RNA guides the complex to a DNA target to cut it. Here, the RNA still directs the complex to the target, but instead of cutting the DNA, it recruits the cell’s transcription machinery to activate gene expression, turning on the gene”, said Leifu Chang, an associate professor of biological sciences who led the Purdue team. “It’s like switching from molecular scissors to a GPS-guided activation switch.”

One study shows that this CRISPR system, using a strand of RNA as a guide, finds specific sections of DNA, known as genes, and attracts the cell’s own gene expression machinery to the location to activate the gene. The second study explains how the molecular complex performs this task, revealing how its structure allows it to recruit RNA polymerase — the enzyme responsible for transcribing DNA into RNA — to initiate gene expression.

Chang, with contributions from postdoctoral researcher Renjian Xiao and Ph.D. student Dan Xie, used a combination of cryo-electron microscopy and biochemical experiments to uncover the structural and mechanistic basis of this RNA-guided gene activation system.

Using cryo-electron microscopy, the researchers visualized the multi-protein complex at near-atomic resolution, revealing how the RNA guide directs the complex to a specific DNA sequence and positions it to engage the cell’s transcription machinery. Biochemical experiments further demonstrated how this interaction triggers gene activation.

“In traditional CRISPR, RNA guides the complex to a DNA target to cut it. Here, the RNA still directs the complex to the target, but instead of cutting the DNA, it recruits the cell’s transcription machinery to activate gene expression,” said Chang, “It’s like switching from molecular scissors to a GPS-guided activation switch.”

The studies also show that this system can activate transcription even at genomic locations that lack a kind of genetic signpost known as a promoter sequence, which is normally required to start gene expression. The findings highlight an unexpected diversification of CRISPR systems in nature, demonstrating that some have evolved to control gene activity rather than cut DNA.

The studies benefited from Purdue’s Cryo-EM Facility and Proteomics Facility and were funded by the National Institutes of Health and the National Science Foundation CAREER Award.

“Our goal is to understand the fundamental mechanisms of RNA-guided molecular machines,” Chang said. “By defining how these systems work at a molecular level, we can lay the groundwork for safer and more versatile genome engineering technologies.”

 

About the Department of Biological Sciences at Purdue University

The Department of Biological Sciences is the largest life sciences department at Purdue University. As part of Purdue One Health, we are dedicated to pioneering scientific discoveries and transformative education at the cutting edge of innovation. From molecules to cells, from tissues to organisms, from populations to ecosystems- we bring together multiple perspectives, integrating across biological scales to advance our understanding of life and tackle the world’s most pressing challenges. Learn more at bio.purdue.edu.

 

Written by: Alisha Willett, Communications Specialist, amwillet@purdue.edu

Contributors: Leifu Chang, lchang18@purdue.edu