RNA Binding Protein CELF2 Regulates Signal-Induced Alternative Polyadenylation by Competing with Enhancers of the Polyadenylation Machinery
RNA Binding Protein CELF2 Regulates Signal-Induced Alternative Polyadenylation by Competing with Enhancers of the Polyadenylation Machinery
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DOI：
10.1016/j.celrep.2019.08.022
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发表时间：
2019-09-10
期刊：
影响因子：
8.8
通讯作者：
Lynch, Kristen W.
中科院分区：
文献类型：
--
作者：
Chatrikhi, Rakesh;Mallory, Michael J.;Lynch, Kristen W.
人mRNA的3' UTR（UTR）在控制蛋白质表达和功能中起关键作用。重要的是，人类信息的3'UTR对于每个基因不是不变的，而是以细胞状态依赖性方式通过替代性聚腺苷酸化（阿帕）形成的，包括响应于T细胞活化。然而，驱动阿帕调节的蛋白质和机制仍然知之甚少。在这里，我们表明，RNA结合蛋白CELF 2控制阿帕的自己的消息在一个信号依赖的方式，通过竞争与核心增强子的多聚腺苷酸化机制结合到RNA。我们进一步表明，CELF 2的结合与阿帕增强子的转录组范围内的重叠，几乎一半的3'UTR，经历T细胞信号诱导的阿帕调节CELF 2依赖的方式。因此，这些研究揭示了CELF 2是T细胞中3'UTR身份的关键调节剂，并证明了CELF 2在调节多聚腺苷酸化位点选择中的另外机制。
The 3' UTR (UTR) of human mRNAs plays a critical role in controlling protein expression and function. Importantly, 3' UTRs of human messages are not invariant for each gene but rather are shaped by alternative polyadenylation (APA) in a cell state-dependent manner, including in response to T cell activation. However, the proteins and mechanisms driving APA regulation remain poorly understood. Here we show that the RNA-binding protein CELF2 controls APA of its own message in a signal-dependent manner by competing with core enhancers of the polyadenylation machinery for binding to RNA. We further show that CELF2 binding overlaps with APA enhancers transcriptome-wide, and almost half of 3' UTRs that undergo T cell signaling-induced APA are regulated in a CELF2-dependent manner. These studies thus reveal CELF2 to be a critical regulator of 3' UTR identity in T cells and demonstrate an additional mechanism for CELF2 in regulating polyadenylation site choice.