High-Resolution RNA Maps Suggest Common Principles of Splicing and Polyadenylation Regulation by TDP-43
Gregor Rot,
Zhen Wang,
Ina Huppertz,
Miha Modic,
Tina Lenče,
Martina Hallegger,
Nejc Haberman,
Tomaž Curk,
Christian von Mering,
Jernej Ule
Affiliations
Gregor Rot
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; Corresponding author
Zhen Wang
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
Ina Huppertz
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany
Miha Modic
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Institute of Stem Cell Research, Helmholtz Center Munich, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany
Tina Lenče
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Institute of Molecular Biology, Ackermannweg 4, 55128 Mainz, Germany
Martina Hallegger
UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Nejc Haberman
UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Tomaž Curk
Faculty of Computer and Information Science, University of Ljubljana, Večna pot 113, 1001 Ljubljana, Slovenia
Christian von Mering
Institute of Molecular Life Sciences and Swiss Institute of Bioinformatics, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Jernej Ule
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Corresponding author
Summary: 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. : 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). Keywords: alternative polyadenylation, TDP-43, RNA map, positional regulatory principles, clustered sequence motifs, alternative splicing, expressRNA, RNAmotifs2, 3′ mRNA sequencing, iCLIP
