An Integrative Study of Protein-RNA Condensates Identifies Scaffolding RNAs and Reveals Players in Fragile X-Associated Tremor/Ataxia Syndrome
An Integrative Study of Protein-RNA Condensates Identifies Scaffolding RNAs and Reveals Players in Fragile X-Associated Tremor/Ataxia Syndrome
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DOI：
10.1016/j.celrep.2018.11.076
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发表时间：
2018-12-18
期刊：
影响因子：
8.8
通讯作者：
Gaetano Tartaglia, Gian
中科院分区：
文献类型：
--
作者：
Cid-Samper, Fernando;Gelabert-Baldrich, Mariona;Gaetano Tartaglia, Gian
最近的证据表明，特定的RNA通过充当RNA结合蛋白（RBP）的支架来促进核糖核蛋白缩合物的形成。我们系统地研究了RNA-RBP相互作用网络，以了解核糖核蛋白组装。我们发现高度接触的RNA是结构化的，具有长UTR，并含有核苷酸重复扩增。在具有这些特性的RNA中，我们鉴定了FMR 1 3' UTR，其具有与脆性X相关震颤/共济失调综合征（FXTAS）有关的CGG扩增。我们研究了FMR 1的结合伙伴在电脑和体外和优先剪接调节TRA 2A进一步表征。在FXTAS细胞模型中，我们验证了TRA 2A-FMR 1相互作用，并研究了其在转录组和转录后水平上的隔离作用。我们发现TRA 2A在FXTAS小鼠模型和死后人类样本中与FMR 1共聚集。我们的综合研究确定了核糖核蛋白聚集体的关键成分，提供了神经退行性疾病的联系，并允许发现治疗靶点。
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.