Zhang lab develops a new imaging technique helps UNC researchers study tiny, time-sensitive biological processes – the crucial underpinnings of human health and disease.
So much of what happens inside cells to preserve health or cause disease is so small or time-sensitive that researchers are just now getting glimpses of the complexities unfolding in us every minute of the day. UNC School of Medicine researchers have discovered one such complexity – a previously hidden mode of RNA regulation vital for bacterial defense against toxic fluoride ions.
Published in the journal Nature Chemical Biology, the discovery opens a new research avenue for developing drugs that target RNA – genetic molecules important for various biological processes, including how genes are regulated.
“Much research to find the underpinnings of health and disease has rightfully focused on proteins, but different forms of RNA have functions we’re just beginning to understand,” said Qi Zhang, PhD, senior author and assistant professor of biochemistry and biophysics. “Our NMR technique is helping us learn more than ever before.”
In 2014, Zhang and colleagues developed a new way to use nuclear magnetic resonance (NMR) imaging to show the shape and motion of RNA at the atomic level over time. This was crucial because RNA is often short-lived and sparsely populated in cells at any given time. The amount of RNA changes over short bursts of time depending on which one of its various roles it is fulfilling. Yet, until now, structural biologists have only visualized RNA as a series of snapshots. Zhang’s technique enables new ways of visualizing RNA, down to its atoms.
“We need this atomic level view because every atomic interaction is important to human health,” said Zhang, who is also a member of the UNC Lineberger Comprehensive Cancer Center. “Scientists have developed similar approaches that work well for proteins and we needed this for RNA, which is crucial for understanding how an RNA serves as a control switch for gene expression.”
In their latest work, Zhang and colleagues studied riboswitches – a class of noncoding RNAs that are not translated from DNA into proteins. Rather, riboswitches control gene expression in response to specific cellular cues. Many bacteria rely on these cues and controls to regulate fundamental cellular function. These switches have been important models for the scientific community’s basic understanding of RNA architecture and ligands – molecules such as drug compounds. Riboswitches have emerged as targets for a new class of very much needed antibacterial drugs.
Here’s the prevailing wisdom of how these riboswitches work: when a cell produces a metabolite or encounters a toxin to a certain level, a sensor on the riboswitch detects this, reshapes the switch’s three-dimensional structure, and sends a signal to turn the responsible gene circuit on or off. This model has been shown in a variety of riboswitches. But when Zhang’s group tried to understand how bacteria use a specific class of these genetic switches – fluoride riboswitches – to kick start their defense mechanism against a toxic level of fluoride ions, they came upon a mystery.
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The National Institutes of Health and the University of North Carolina at Chapel Hill funded this work.
Other authors of the Nature Biological Chemistry paper are Bo Zhao, graduate student in the department of chemistry in the UNC College of Arts and Sciences, Sharon Guffy, graduate student in the department of biochemistry and biophysics, and Benfeard Williams, PhD, former graduate student in the department of biochemistry and biophysics in the UNC School of Medicine.
Story courtesy of Mark Derewicz, Communications Manager at UNC Health Care
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