A*STAR Scientists Unveil Novel Technique to Decipher RNA Structure’s Impact on Health and Disease

In a groundbreaking advancement that promises to reshape our understanding of gene regulation, researchers at the ASTAR Genome Institute of Singapore (ASTAR GIS) have unveiled a pioneering technique named sm-PORE-cupine. This novel method enables scientists to examine individual RNA molecules in their entirety, revealing the intricate folding patterns and structures that govern their behavior within cells—a crucial leap forward in RNA biology with profound implications for disease research and therapeutic innovation.

RNA, traditionally viewed merely as the intermediary messenger carrying genetic instructions from DNA to synthesize proteins, has emerged as a molecule of remarkable structural versatility. Unlike DNA’s relatively rigid double helix, RNA strands are highly flexible and capable of adopting myriad secondary and tertiary conformations. These conformations orchestrate diverse cellular processes by modulating protein synthesis efficiency, RNA lifespan, and interactions with cellular machinery. However, the dynamic and pliable nature of RNA has long thwarted detailed structural analyses at the single-molecule level.

Existing techniques to probe RNA structure typically aggregate signals across populations of molecules, yielding averaged structural snapshots that obscure the heterogeneity within even identical sequences. This averaging masks subtle but functionally significant folding differences among RNA transcripts derived from the same gene, leaving a critical gap in our molecular understanding of RNA-mediated regulation.

Addressing this unmet challenge, the sm-PORE-cupine approach ingeniously integrates site-specific chemical labeling with nanopore-based direct RNA sequencing. By employing optimized chemical reagents that selectively attach to unpaired, solvent-exposed RNA bases, this method tags structural features that serve as molecular beacons. When these chemically modified RNAs pass through nanopores—protein-based nanoscale channels capable of threading single nucleic acid strands—the sequencing platform detects characteristic disruptions in ionic current, decoding both the nucleotide sequence and structural marks in real time.

The capacity of sm-PORE-cupine to read full-length RNA molecules enables unprecedented resolution in structural profiling, capturing the folding landscapes of individual RNA transcripts without ensemble averaging. Advanced computational frameworks analyze the complex nanopore signal patterns to reconstruct RNA structural states with remarkable precision, revealing diverse conformations coexisting within cell samples.

This technological breakthrough has already yielded striking biological insights. Researchers have observed that alternative folding of RNA molecules from the same genetic locus influences critical parameters such as translational efficiency and degradation rates. These findings firmly link RNA structural heterogeneity to gene regulatory mechanisms that control protein abundance and RNA stability, processes integral to cellular homeostasis and response.

Understanding the nuances of RNA folding has far-reaching consequences, particularly in the context of diseases where gene regulation is disrupted. The new method sheds light on how RNA structures modulate viral life cycles, including the pathogenic SARS-CoV-2 virus, offering fresh perspectives on viral replication and host-virus interactions. Beyond virology, sm-PORE-cupine’s ability to decode RNA dynamics extends to broader pathogenic organisms, paving the way for novel RNA-targeted therapeutics.

The ramifications of this research extend into drug discovery and personalized medicine. By elucidating the structural underpinnings of gene expression regulation, this approach identifies potential RNA conformational states that serve as therapeutic targets. Consequently, sm-PORE-cupine could accelerate the development of antiviral drugs, antifungal agents, and precision therapies that exploit RNA structural vulnerabilities.

Dr. Wan Yue, Executive Director at ASTAR GIS and lead author of the study, emphasizes the significance of this advancement, stating, “Our work at ASTAR GIS opens new avenues to dissect RNA folding mechanisms at an unprecedented scale. By decoding how RNA molecules fold diversely and regulate gene expression, we lay a scientific foundation that could transform diagnostics and treatment paradigms.”

Complementing this vision, Dr. Niranjan Nagarajan, Associate Director, AI and Compute, and Senior Group Leader at A*STAR GIS, highlights the unique capabilities unlocked by nanopore sequencing technology in this domain: “Leveraging direct RNA nanopore sequencing allows us to capture RNA’s dynamic shape-shifting properties one molecule at a time. This innovative fusion of chemistry and computational analytics sets a new benchmark for transcriptomic studies.”

The integration of sm-PORE-cupine within the genomic research infrastructure at A*STAR GIS not only advances fundamental science but also serves as a catalyst for future biotechnological and clinical applications. Published recently in the esteemed journal Nature Methods, this work has already garnered attention for its potential to revolutionize how RNA biology is studied and exploited for human health benefits.

As we stand on the cusp of a new era in molecular genetics, sm-PORE-cupine exemplifies the power of converging multidisciplinary technologies to unravel the complexity of life’s blueprint. By illuminating the structural choreography of RNA molecules, this technique offers a compelling vision of precision medicine rooted in the molecular fabric of cells, fostering hope for more effective interventions against a myriad of diseases.

News Publication Date: Not explicitly specified (related to recent publication in 2026).

Web References:

• A*STAR Genome Institute of Singapore: www.a-star.edu.sg/gis
• Original Article in Nature Methods: https://www.nature.com/articles/s41592-026-03069-y
• DOI: 10.1038/s41592-026-03069-y

References:

• The primary publication describing sm-PORE-cupine in Nature Methods.