High-Resolution RNA Maps Suggest Common Principles of Splicing and Polyadenylation Regulation by TDP-43

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. [Display omitted] •TDP-43 regulates competing poly(A) sites in a highly position-dependent manner•expressRNA is a new platform for analysis of alternative polyadenylation and splicing•RNAmotifs2 is a cluster motif analysis platform integrated with expressRNA•Regulation of pre-mRNA processing might follow common position-dependent principles Rot et al. investigate how TDP-43 regulates alternative polyadenylation in HEK293 cells. This defined position-dependent regulatory principles with high-resolution RNA maps. The authors provide an integrative computational platform for comprehensive analysis of alternative splicing and alternative polyadenylation (expressRNA), as well as software for positional analysis of clustered sequence motifs (RNAmotifs2).