Computational approaches to characterize RNP granules

Ribonucleoprotein granules (RNP granules) are liquid-liquid phase separated complexes composed mainly by proteins and RNA. They are responsible of many processes involved in RNA regulation. Alterations in the dynamics of these proteinRNA complexes are associated with the appearance of several neurodegenerative disorders such as Amyotrophic Lateral Sclerosis ALS or Fragile X Tremor Ataxia Syndrome FXTAS. Yet, many aspects of their organization as well as the specific roles of the RNA on the formation and function of these complexes are still unknown. In order to study RNP granules structure and formation, we integrated several state of the art high-throughput datasets. This includes protein and RNA composition obtained from RNP pull-downs, protein-RNA interaction data from eCLIP experiments and transcriptome-wide secondary structure information (produced by PARS). We used network analysis and clustering algorithms to understand the fundamental properties of granule RNAs. By integrating these properties, we produced a model to identify scaffolding RNA. Scaffolding RNAs are able to recruit many protein components into RNP granules. We found that the main protein components of stress granules (a kind of RNP granules) are connected through protein-RNA interactions. We also analyzed the contribution of RNA-RNA interactions and RNA post-transcriptional modifications on the granule internal organization. We applied these findings to understand the biochemical pathophysiology of FXTAS disease, employing as well some novel experimental data. In FXTAS, a mutation on the FMR1 gene produces a 5´microsatellite repetition that enhances its scaffolding ability. This mutated mRNA is able to sequester some important proteins into nuclear RNP granules, such as TRA2A (i.e. a splicing factor), impeding their normal function and therefore producing some symptoms associated with the progress of the disease. The better understanding of the principles governing granules formation and structure will enable to develop novel therapies (e.g. aptamers) to mitigate the development of several neurodegenerative diseases. Los gránulos ribonucleoproteicos (gránulos RNP, por sus siglas en inglés) son complejos producidos mediante separación líquido-líquido y están constituidos principalmente por proteínas y ARN. Son responsables de numerosos procesos involucrados con la regulación del ARN. Alteraciones en la dinámica de estos complejos de proteínas y ARN están asociadas con la aparición de d