New technology reveals how RNA shapes influence protein production and stability

Researchers from A*STAR Genome Institute of Singapore (A*STAR GIS) have developed a new method, called ‘sm-PORE-cupine’, to study individual RNA molecules and reveal how their structures influence gene regulation, a fundamental process that affects how cells function in health and disease.

RNA is best known for carrying genetic instructions from DNA to make proteins. However, RNA does more than act as a messenger. Like a string that can bend, fold and interact with other molecules, RNA can adopt different shapes that affect how it behaves in the cell. These shapes can influence how efficiently proteins are produced, how long RNA molecules last, and how diseases such as viral infections progress.

Until now, studying these structures in detail has been difficult because RNA is highly flexible and dynamic. Most existing methods only provide an average picture across many RNA molecules, making it harder to see how individual RNA molecules may fold differently, even when they come from the same gene.

Reading RNA one molecule at a time

To address this challenge, the A*STAR GIS team developed a new technology called sm-PORE-cupine, which combines chemical labelling with direct RNA sequencing to detect changes in RNA structure.

The technology uses optimized chemical compounds to mark non-paired RNA bases, which are parts of the molecule that are more exposed. These marks act like signposts, giving researchers clues about how the RNA is folded. Nanopore direct RNA sequencing then reads the full-length RNA molecules, allowing scientists to study their structures in greater detail.

By applying advanced computational analysis, the team could interpret these signals at single-molecule resolution, helping them see how RNAs from the same gene can fold and behave differently.

Linking RNA structure to cell behavior

Using sm-PORE-cupine, the researchers observed that RNA molecules can adopt different structures, and that these differences are linked to how efficiently proteins are produced and how quickly RNAs are degraded.

This is important because protein production and RNA stability are key parts of gene regulation. When these processes go wrong, they can contribute to disease. By giving scientists a clearer view of how individual RNA molecules behave, the new method provides deeper insight into how RNA structure affects cellular function.

Opening new paths for disease research and drug discovery

This research also provides new insights into how RNA structures influence viral function, including in viruses such as SARS-CoV-2, as well as gene regulation in pathogenic organisms.

These findings could help researchers identify new RNA-based therapeutic targets and support the development of antiviral drugs, antifungal treatments and RNA-targeted therapies. In the longer term, the technology and knowledge generated could contribute to better disease diagnostics, drug discovery and precision medicine by helping scientists better understand how RNA structure influences health and disease.

At A*STAR GIS, we pursue deep scientific understanding to enable better solutions for health and disease. By uncovering how RNA molecules adopt different structures and how these structures influence gene regulation, this work lays the foundation for more precise approaches to diagnosis and treatment.”

Dr. Wan Yue, Executive Director,  A*STAR GIS 

Co-lead author Dr Niranjan Nagarajan, Associate Director, AI and Compute, and Senior Group Leader, Laboratory of Metagenomic Technologies and Microbial Systems, A*STAR GIS, added, “By leveraging direct RNA sequencing using nanopores, we now have a unique capability to study the dynamics of how RNAs shape-shift. This work builds on A*STAR GIS’ significant strengths in nanopore sequencing-based analytics.”

Their work was recently published in Nature Methods.