Gene Function and Evolution

In my CRG/ICREA laboratory we combine computational and experimental work to unravel protein interactions with coding and non-coding RNAs.  As a large number of proteins have the ability to interact with RNA, we strive to understand what are their specific targets and biological functions. To this aim, we develop algorithms for high-throughput predictions of protein-RNA interactions.  Hot topics in which my group played a leading role: We focused on Xist long non-coding RNA that regulates genomic imprinting in a process called X-chromosome inactivation. We built a new theoretical method and predicted Xist physical interactors that were confirmed experimentally using the state-of-the-art technique, enhanced CrossLinking and Immunoprecipitation (eCLIP). We are particularly interested in studying RNA structure to unveil its role in functional interactions and we built a novel approach that identifies single and double-stranded regions within transcripts. We also investigate RNA-binding proteins that coalesce in large assemblies or granules. Our results indicate that uncontrolled sequestration of protein and RNA material in granules is toxic, which opens up the avenue for further investigations in the area of neurodegeneration. In 2017 we discovered that two components of granules, TIAR and ELAVL1, regulate the expression of SNCA protein and showed that their activity has consequences for the onset and development Parkinson’s disease.

• Post-transcriptional networks involved in Parkinson’s disease.   We investigated the post-transcriptional regulation of alpha-synuclein (SNCA) implicated in Parkinson’s disease. In agreement with our computational predictions, we found that TIAR positively regulates SNCA inducing changes in abundance that are compatible with those observed in idiopathic Parkinsonism.
• Protein interactome of large RNAs. Based on catRAPID calculations, omiXcore allows predictions of local (RNA contacts) and global (overall binding propensity) interactions of RNA-binding proteins with RNA molecules. We calibrated omiXcore using enhanced UV Cross-Linking and ImmunoPrecipitation (eCLIP) and optimized the webserver for calculations of interactions with long intergenic non-coding RNA (lincRNA).
• Non-coding RNAs scaffold protein interactions. We predicted the largest lncRNA-protein interaction network and assess, for the first time, the role of lncRNAs in scaffolding protein complexes. By identifying hundreds of lncRNAs that bind to protein complexes, our findings suggest that RNA-mediated scaffolding is a widespread mechanism in human cells.
• Nucleotide expansions and disease. Neuronal intranuclear hyaline inclusion disease (NIHID) is a rare disorder showing clinical overlap with Fragile X–associated tremor/ataxia syndrome (FXTAS). While CGG repeats have been shown to attract RBPs in granules causing FXTAS, our result suggest that other nucleotide expansions trigger NIHID.