Measuring RNA modifications opens new research avenues for cancer detection

Researchers at the Centre for Genomic Regulation (CRG) have developed a new method to measure the abundance of RNA modifications in much finer detail than previously possible. The findings will advance research efforts in the field of cancer detection, amongst others.

RNA, or ribonucleic acid, is a molecule similar to DNA. One of its functions is to act as the intermediary code used by cells to transfer information from the genome into proteins by translation. It is known that RNA molecules are teeming with chemical modifications, but where they are, what they do and what effect this has on the overall biology of living organisms is an open question.

In recent years, the enzymes that regulate RNA modifications have been linked to critical biological functions ranging from learning and memory, intergenerational inheritance, the immune system and embryogenesis. Studying RNA modifications is particularly of interest for cancer, providing potential new therapeutic targets to detect or treat the disease. For example, researchers recently announced a drug that can inhibit enzymes that modify RNA and are linked to the initiation and maintenance of acute myeloid leukaemia.

The most technologically advanced methods used to measure RNA modifications involve using nanopore sequencing technologies, which analyse RNA fragments in real time. However, current algorithms used to analyse nanopore sequencing data only detects if a region of an RNA transcript is modified, but cannot predict whether individual molecules are modified. Current algorithms have also been largely limited to detecting a handful of RNA modifications in nanopore sequencing data. This means researchers have lacked the tools to measure or map RNA modifications in detail.

In a new paper published today in Nature Biotechnology, researchers overcome this barrier by describing a new method that can detect and quantify many different types of RNA modifications at single molecule resolution. The research team developed a novel algorithm to predict the stoichiometry of RNA modifications by identifying modifications present in individual RNA molecules, sequenced using nanopore technologies.

The work was led by Eva Novoa, a junior Group Leader at the CRG who studies the ‘epitranscriptome’, a term used to describe the field of RNA modifications. “Both DNA and RNA molecules have chemical modifications, but RNA molecules have more and we still do not know what they do. For decades these were thought to be passive, structural features that were unlikely to have any regulatory function. With time, evidence has shown that RNA modifications play an important role in human development and physiology. Our method will help reveal the extent of this,” she says.

According to the authors, the new method can be used to study the biological functions of diverse RNA modification types that could not be studied before. “We have multiple highly diverse research lines in our lab where we aim to apply these findings and software innovations to, including vertebrate embryogenesis, intergenerational inheritance, immune responses, and cancer detection,” concludes Eva Novoa.