Taliaferro J Matthew, Vidaki Marina, Oliveira Ruan, Olson Sara, Zhan Lijun, Saxena Tanvi, Wang Eric T, Graveley Brenton R, Gertler Frank B, Swanson Maurice S, Burge Christopher B
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Mol Cell. 2016 Mar 17;61(6):821-33. doi: 10.1016/j.molcel.2016.01.020. Epub 2016 Feb 18.
Spatial restriction of mRNA to distinct subcellular locations enables local regulation and synthesis of proteins. However, the organizing principles of mRNA localization remain poorly understood. Here we analyzed subcellular transcriptomes of neural projections and soma of primary mouse cortical neurons and two neuronal cell lines and found that alternative last exons (ALEs) often confer isoform-specific localization. Surprisingly, gene-distal ALE isoforms were four times more often localized to neurites than gene-proximal isoforms. Localized isoforms were induced during neuronal differentiation and enriched for motifs associated with muscleblind-like (Mbnl) family RNA-binding proteins. Depletion of Mbnl1 and/or Mbnl2 reduced localization of hundreds of transcripts, implicating Mbnls in localization of mRNAs to neurites. We provide evidence supporting a model in which the linkage between genomic position of ALEs and subcellular localization enables coordinated induction of localization-competent mRNA isoforms through a post-transcriptional regulatory program that is induced during differentiation and reversed in cellular reprogramming and cancer.
信使核糖核酸（mRNA）在不同亚细胞位置的空间限制能够实现蛋白质的局部调控和合成。然而，mRNA定位的组织原则仍知之甚少。在这里，我们分析了原代小鼠皮质神经元以及两种神经元细胞系的神经突起和胞体的亚细胞转录组，发现可变最后外显子（ALE）通常赋予异构体特异性定位。令人惊讶的是，基因远端的ALE异构体定位于神经突的频率比基因近端异构体高四倍。定位异构体在神经元分化过程中被诱导，并富含与类肌肉盲（Mbnl）家族RNA结合蛋白相关的基序。Mbnl1和/或Mbnl2的缺失减少了数百种转录本的定位，表明Mbnl参与了mRNA向神经突的定位。我们提供的证据支持一种模型，即ALE的基因组位置与亚细胞定位之间的联系通过一个在分化过程中被诱导且在细胞重编程和癌症中被逆转的转录后调控程序，实现了具有定位能力的mRNA异构体的协同诱导。
