An integrative study of protein-RNA condensates identifies scaffolding RNAs and reveals players in fragile X-associated tremor/ataxia syndrome

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• dc.contributor.author Cid Samper, Fernando, 1991-
• dc.contributor.author Gelabert-Baldrich, Mariona
• dc.contributor.author Lang, Benjamin
• dc.contributor.author Lorenzo Gotor, Maria de las Nieves
• dc.contributor.author Ponti, Riccardo delli
• dc.contributor.author Severijnen, Lies-Anne W.F.M.
• dc.contributor.author Bolognesi, Benedetta
• dc.contributor.author Gelpi, Ellen
• dc.contributor.author Hukema, Renate K.
• dc.contributor.author Botta Orfila, Teresa
• dc.contributor.author Tartaglia, Gian Gaetano
• dc.date.accessioned 2019-11-04T08:47:49Z
• dc.date.available 2019-11-04T08:47:49Z
• dc.date.issued 2018
• dc.description.abstract Recent 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.
• dc.description.sponsorship The research leading to these results has been supported by the European Research Council (RIBOMYLOME_309545), Spanish Ministry of Economy and Competitiveness (BFU2014-55054-P and BFU2017-86970-P), and “Fundació La Marató de TV3” (PI043296). We acknowledge support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013-2017’. We acknowledge the support of the CERCA Programme, Generalitat de Catalunya and Spanish Ministry for Science and Competitiveness (MINECO) to the EMBL partnership.
• dc.format.mimetype application/pdf
• dc.identifier.citation Cid-Samper F, Gelabert-Baldrich M, Lang B, Lorenzo-Gotor N, Ponti RD, Severijnen LWFM et al. An integrative study of protein-RNA condensates identifies scaffolding RNAs and reveals players in fragile X-associated tremor/ataxia syndrome. Cell Rep. 2018; 25(12):3422-34. DOI: 10.1016/j.celrep.2018.11.076
• dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2018.11.076
• dc.identifier.issn 2211-1247
• dc.identifier.uri http://hdl.handle.net/10230/42588
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Cell Reports. 2018; 25(12):3422-34
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-55054-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-86970-P
• dc.rights © 2018 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Phase separation
• dc.subject.keyword Scaffolding RNA
• dc.subject.keyword CGG repeat expansion
• dc.subject.keyword FMR1 premutation
• dc.subject.keyword Fragile X-associated tremor/ataxia syndrome
• dc.subject.keyword FXTAS
• dc.subject.keyword RNA aggregates
• dc.subject.keyword RNA binding proteins
• dc.subject.keyword RBP
• dc.subject.keyword TRA2A splicing regulator
• dc.subject.keyword Neurodegeneration
• dc.title An integrative study of protein-RNA condensates identifies scaffolding RNAs and reveals players in fragile X-associated tremor/ataxia syndrome
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion