Rot Gregor, Wang Zhen, Huppertz Ina, Modic Miha, Lenče Tina, Hallegger Martina, Haberman Nejc, Curk Tomaž, von Mering Christian, Ule Jernej
Institute of Molecular Life Sciences and Swiss Institute of Bioinformatics, Winterthurerstrasse 190, 8057 Zurich, Switzerland; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Institut de Biologie de l'ENS (IBENS), 46 rue d'Ulm, Paris 75005, France.
Cell Rep. 2017 May 2;19(5):1056-1067. doi: 10.1016/j.celrep.2017.04.028.
Many RNA-binding proteins (RBPs) regulate both alternative exons and poly(A) site selection. To understand their regulatory principles, we developed expressRNA, a web platform encompassing computational tools for integration of iCLIP and RNA motif analyses with RNA-seq and 3' mRNA sequencing. This reveals at nucleotide resolution the "RNA maps" describing how the RNA binding positions of RBPs relate to their regulatory functions. We use this approach to examine how TDP-43, an RBP involved in several neurodegenerative diseases, binds around its regulated poly(A) sites. Binding close to the poly(A) site generally represses, whereas binding further downstream enhances use of the site, which is similar to TDP-43 binding around regulated exons. Our RNAmotifs2 software also identifies sequence motifs that cluster together with the binding motifs of TDP-43. We conclude that TDP-43 directly regulates diverse types of pre-mRNA processing according to common position-dependent principles.
许多RNA结合蛋白（RBP）同时调节可变外显子和聚腺苷酸化（poly(A)）位点的选择。为了理解它们的调控原理，我们开发了expressRNA，这是一个网络平台，包含用于整合iCLIP和RNA基序分析与RNA测序和3' mRNA测序的计算工具。这在核苷酸分辨率上揭示了“RNA图谱”，描述了RBP的RNA结合位置与其调控功能的关系。我们使用这种方法来研究参与多种神经退行性疾病的RBP——TDP-43如何在其调控的poly(A)位点周围结合。靠近poly(A)位点的结合通常会抑制，而在更下游的结合则会增强该位点的使用，这与TDP-43在调控外显子周围的结合情况相似。我们的RNAmotifs2软件还识别出与TDP-43的结合基序聚集在一起的序列基序。我们得出结论，TDP-43根据共同的位置依赖性原则直接调节多种类型的前体mRNA加工。
