Researchers at the Italian Institute of Technology (IIT) in Genoa and the European Molecular Biology Laboratory (EMBL) in Grenoble have revealed how the process of gene regulation can be modulated using small molecules.
The study, published in Nature Communications, lays the foundations for a possible future identification of new drugs that can act directly on mutations or genetic modifications that alter the process of gene expression, thus intervening, for example, on the onset of tumours or genetic diseases. The proper functioning of cells depends to a large extent on the ability to control gene expression: a complex process through which information contained in DNA is copied into RNA to give rise to all proteins and most of the cell’s regulatory molecules. The study was coordinated by Marco De Vivo, principal investigator at the Molecular Modeling & Drug Discovery Lab and associate director for Computation at IIT in Genoa, and Marco Marcia, group leader at EMBL in Grenoble.
The study brought together the expertise of EMBL and the Grenoble Structural Biology Partnership in biochemistry, biophysics and structural biology, which allowed X-ray photographs of the process to be obtained. For this purpose, the highly automated MASSIF-1 beamline of the EMBL and the European Radiation Synchrotron Facility (ESRF) was used. These were then joined by the computational simulation skills of the IIT, thanks to which it was possible to study the details of the chemical-physical interactions between the molecules involved. The study focused on splicing, one of the key control levels of the gene expression process during which molecular machines in the cell ‘cut and paste’ specific RNA sequences to create functional versions. These ‘mature’ versions of RNA perform various functions, including acting as instructions for protein production or directly as regulators of various cellular processes.
“Studying the RNA splicing reaction, i.e. “cutting and stitching”, is very complex because of both the chemical reactions and the molecular actors involved, such as RNA, proteins, ions and water molecules. Thanks to modern molecular simulation techniques, we have gained a detailed understanding of what happens, and how we can intervene to modulate splicing. Our study has already allowed us to synthesise newdrug-like molecules that can modulate splicing in a new, specific and very effective way,’ Marco De Vivo commented.
Molecules that have been the subject of a patent filed by IIT and EMBL researchers, with the support of EMBL’s technology transfer office. The future improvement of such compounds could, according to the researchers, make it possible to modulate the production of proteins that originate from defective or mutated genes. Visualising at the atomic level the modulation of splicing is exciting. It allows us to control one of the fundamental reactions that enables life. In the future, by continuing to integrate our experimental biological studies with the chemical and computational studies of our collaborators, we will aim at an ambitious goal, that of developing new antibacterial and anti-cancer drugs,’ Marco Marcia emphasised. The research is part of the Italian Institute of Technology’s RNA Flagship initiative dedicated to the development and application of new RNA-based technologies.