RNA modifications (mRNAs) are the post-synthesis changes to the chemical composition of RNA molecules that alter their function or stability. Understanding how these RNA modifications work could open the door to new ways of treating diseases. Take for example RNA methylation of adenine, a reversible modification to RNA that produces N6-methyladenosine (m6A) that can impact numberous biological processes. Knowing how this modification works could be exploited to treat brain cancer and other nervous system conditions. However, this first requires knowing what m6A targets and the processes it regulates which is where the EU-funded EpiMethFly project steps in. “Our aim is to clarify the role of m6A in the nervous system, particularly during brain development, and discover its contribution to such pathological conditions as cognitive deficits and brain cancer,” says Alessandro Quattrone, a researcher at the University of Trento and EpiMethFly project coordinator. The research was undertaken with the support of the Marie Skłodowska-Curie Actions. Quattrone supervised the work of Alessia Soldano, a postdoc at the Laboratory of Translational Genomics and Marie Skłodowska-Curie individual fellow.
How m6A affects the nervous system
The project set out to address the central question of how m6A affects the biology of the nervous system and what molecular mechanisms cause this affect. To find out, Soldano conducted her research using the fruit fly Drosophila melanogaster. “We are particularly proud of the fact that there wasn’t any fruit fly research happening in our department when we started this project, meaning I had to establish the model from scratch,” explains Soldano. “Although it was challenging, within just a few months we had everything up and running.” By genetically altering the m6A machinery in a time- and tissue-specific manner, researchers were able to make some important discoveries. “First, we clarified that during the fruit fly’s brain development, m6A is required to prevent axonal overgrowth,” notes Soldano. “Secondly, we demonstrated that the m6A mark influences the biology of mRNA by affecting the interaction between one RNA binding protein and its target mRNAs.” According to Soldano, this protein is important because, in humans, its counterpart is mutated in a widespread genetic form of mental retardation.
The potential for a big impact
The results achieved during the EpiMethFly project have the potential to have a big impact on future research and medicine. “Having identified the role m6A plays in axon growth and guidance paves the road to further identifying m6A targets involved in this process,” says Soldano. “These results could also lay the groundwork for developing therapeutic targets for a range of neurodevelopmental diseases.” Soldano is currently working to establish an independent research group to continue working on this topic. She is also applying for various grants. “The Marie Skłodowska-Curie Action has been of great importance for my career,” she concludes. “It allowed me to develop a competitive project that led to important results that will greatly contribute to the field of RNA biology.”
EpiMethFly, RNA, RNA modification, nervous system, brain cancer, neurodevelopmental disease, RNA methylation in adenine, m6A, fruit fly