Exceptional research recordings display RNA switching “on” and “off”

RNA switches (also known as riboswitches) control which genes are turned “on” and “off”, much like a light switch. Although this appears to be a straightforward process, biologists have been astonished by the inner workings of these switches for decades.

Now, scientists from Northwestern University and the University of Albany have discovered that one component of RNA seamlessly invades and disperses another part of the same RNA, allowing the structure to change shape quickly and drastically. This technique, known as “strand displacement,” appears to convert a genetic expression from “on” to “off.”

The scientists achieved this discovery by seeing a slow-motion simulation of a riboswitch up close and in action using a simulation they presented the year before. The new simulation, which is known as R2D2 (short for “reconstructing RNA dynamics from data”), models RNA in three dimensions as it attaches to a chemical, interacts along its length, and folds to switch a gene “on” or “off.”

The discoveries could have ramifications for the development of new RNA-based diagnostics and the development of effective medications that target RNA to cure illness and disease.

The findings were published on March 28^th, 2022, in the journal Nucleic Acids Research (NAR), which has classified the work as a “Breakthrough Article.” NAR reserves “Breakthrough Article” status for the most high-impact studies countering long-standing nucleic acid research questions.

We have found this strand displacement mechanism occurring in other types of RNA molecules, indicating this might be a potential generality of RNA folding. We are starting to find similarities among different types of RNA molecules, which could eventually lead to RNA design rules for folding and function.”

Julius B. Lucks, Study Co-Lead, Northwestern University

Lucks is a member of the Center for Synthetic Biology and the Chemistry of Life Processes Institute, as well as a professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering. He and Alan Chen, an associate professor of chemistry at the University of Albany in New York, co-led the research.

R2D2’s “groundbreaking approach”

Although RNA folding occurs more than 10 quadrillion times every second in the human body—every moment a gene is transcribed in a cell—researchers know relatively little about it. Lucks and Chen revealed R2D2 in an article published in the journal Molecular Cell last year to better visualize and comprehend the cryptic but critical mechanism.

R2D2 uses a technology platform built at Lucks’ lab to record data about RNA folding as it is created. The data is then mined and organized using computer methods, indicating where the RNA folds and what occurs after it folds. A former Lucks student, Angela Yu used this information to create accurate recordings of the folding process using computer models.

Dr Francis Collins, director of the National Institutes of Health, states in his February 2021 blog, “What’s so groundbreaking about the R2D2 approach…is that it combines experimental data on RNA folding at the nucleotide level with predictive algorithms at the atomic level to simulate RNA folding in ultra-slow motion.”

“While other computer simulations have been available for decades, they have lacked much-needed experimental data of this complex folding process to confirm their mathematical modeling,” he added.

Long-distance communication

The new movies model a riboswitch from Bacillus subtilis, a common bacteria found in soil. Lucks’ and Chen’s previous simulations revealed the folding of an ancient RNA called SRP.

Riboswitches are made up of two fundamental components. One of the parts binds to a substance. The second portion then enables the RNA to fold into a framework that enables it to control gene expression, based on how the chemical is bound. These two sections are interwoven and overlapped in many riboswitches, but not in Bacillus subtilis.

Many diseases are likely caused by something going awry at the RNA level. The more we know about this, the better we can design RNA targeting drugs and RNA therapeutics.”

Julius Lucks, Synthetic Biologist, Northwestern University

“What’s strange is that they are separated by a long distance, but the bound molecule can cause large functional changes,” Lucks said. “If the chemical binds at one end, then how is that communicated downstream to the other end of the RNA? It’s been a mystery.”

The riboswitch, according to Lucks, Chen, and their colleagues, communicates downstream via the strand displacement process. The strand exchange process causes structural switching between “on” and “off” states about chemical interaction.

Optimizing RNA for drugs, diagnostics

Lucks believes that with this new knowledge, the stage is set for optimizing the riboswitch to perform valuable activities. For example, the switch might be used to turn “on” synthetic biology-based diagnostics in the existence of an environmental toxin. Scientists will acquire lessons from researching this riboswitch that could result in new ways for developing RNA-targeted medicines or new antibiotic classes.

Many diseases are likely caused by something going awry at the RNA level. The more we know about this, the better we can design RNA targeting drugs and RNA therapeutics.”

Julius Lucks, Synthetic Biologist, Northwestern University

Video Credit: Northwestern University