SummaryRecent evidence indicates that specific RNAs promote the formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs). We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly contacted RNAs are structured, have long UTRs, and contain nucleotide repeat expansions. Among the RNAs with such properties, we identified the FMR1 3′ UTR that harbors CGG expansions implicated in fragile X-associated tremor/ataxia syndrome (FXTAS). We studied FMR1 binding partners in silico and in vitro and prioritized the splicing regulator TRA2A for further characterization. In a FXTAS cellular model, we validated the TRA2A-FMR1 interaction and investigated implications of its sequestration at both transcriptomic and post-transcriptomic levels. We found that TRA2A co-aggregates with FMR1 in a FXTAS mouse model and in post-mortem human samples. Our integrative study identifies key components of ribonucleoprotein aggregates, providing links to neurodegenerative disease and allowing the discovery of therapeutic targets.

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Ribonucleoprotein (RNP) granules are composed of RNA-binding proteins (RBPs) and a part of the transcriptome that is still uncharacterized. We performed a largescale study of interaction networks and discovered that RBPs aggregating in RNP granules share specific RNA partners with high structural content, long untranslated regions (UTRs) and nucleotide repeat expansions. Our analysis suggests that RNAs can promote phase-separations in the cell by acting as scaffolds for protein assembly.In a proof-of-concept experiment, we investigated the scaffolding ability of CGG repeats contained in the 5' UTR of FMR1 transcript implicated in Fragile Xassociated Tremor / Ataxia Syndrome (FXTAS). Using a novel high-throughput approach we identified RBPs recruited by FMR1 5' UTRs of different lengths. We employed human primary tissues as well as primate and mouse models of FXTAS to characterize the sequestration of a previously unreported partner, TRA2A, and consequent impairment of splicing pathways associated with mental retardation and intellectual disability.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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