ELAV and FNE Determine Neuronal Transcript Signatures through EXon-Activated Rescue
ELAV and FNE Determine Neuronal Transcript Signatures through EXon-Activated Rescue
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DOI：
10.1016/j.molcel.2020.09.011
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发表时间：
2020-10-01
期刊：
影响因子：
16
通讯作者：
Hilgers, Valerie
中科院分区：
文献类型：
--
作者：
Carrasco, Judit;Rauer, Michael;Hilgers, Valerie
替代RNA变体的产生有助于基因表达的组织特异性调控。在动物神经系统中，向远端转录终止位点的系统性转移产生对神经元发育和功能至关重要的转录特征。在这里，我们报道，在果蝇中，高度保守的蛋白ELAV全局调控神经元3'端加工的所有位点，并在体内直接结合靶mrna的近端聚腺苷化位点。我们发现了一种内源性的功能基因拯救策略，在ELAV功能丧失的背景下保护神经元RNA特征。当不被ELAV直接抑制时，编码ELAV平行FNE的转录本获得一个迷你外显子，产生一个新的蛋白，能够转运到细胞核，并挽救ELAV介导的选择性聚腺苷化和选择性剪接。我们提出外显子激活的功能修复是一种更广泛的机制，它确保了由效应器的层次而不是冗余调节的过程的稳健性。
The production of alternative RNA variants contributes to the tissue-specific regulation of gene expression. In the animal nervous system, a systematic shift toward distal sites of transcription termination produces transcript signatures that are crucial for neuron development and function. Here, we report that, in Drosophila, the highly conserved protein ELAV globally regulates all sites of neuronal 3' end processing and directly binds to proximal polyadenylation sites of target mRNAs in vivo. We uncover an endogenous strategy of functional gene rescue that safeguards neuronal RNA signatures in an ELAV loss-of-function context. When not directly repressed by ELAV, the transcript encoding the ELAV paralog FNE acquires a mini-exon, generating a new protein able to translocate to the nucleus and rescue ELAV-mediated alternative polyadenylation and alternative splicing. We propose that exon-activated functional rescue is a more widespread mechanism that ensures robustness of processes regulated by a hierarchy, rather than redundancy, of effectors.