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Nuclear matrix protein Matrin3 regulates alternative splicing and forms overlapping regulatory networks with PTB.


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Authors

Coelho, Miguel B 
Attig, Jan 
Bellora, Nicolás 
König, Julian 
Hallegger, Martina 

Abstract

Matrin3 is an RNA- and DNA-binding nuclear matrix protein found to be associated with neural and muscular degenerative diseases. A number of possible functions of Matrin3 have been suggested, but no widespread role in RNA metabolism has yet been clearly demonstrated. We identified Matrin3 by its interaction with the second RRM domain of the splicing regulator PTB. Using a combination of RNAi knockdown, transcriptome profiling and iCLIP, we find that Matrin3 is a regulator of hundreds of alternative splicing events, principally acting as a splicing repressor with only a small proportion of targeted events being co-regulated by PTB. In contrast to other splicing regulators, Matrin3 binds to an extended region within repressed exons and flanking introns with no sharply defined peaks. The identification of this clear molecular function of Matrin3 should help to clarify the molecular pathology of ALS and other diseases caused by mutations of Matrin3.

Description

Keywords

Matrin3, PTB, alternative splicing, Alternative Splicing, Computational Biology, DNA Primers, Electrophoresis, Polyacrylamide Gel, Gene Expression Profiling, Gene Regulatory Networks, HEK293 Cells, HeLa Cells, Humans, Microarray Analysis, Nuclear Matrix-Associated Proteins, Polypyrimidine Tract-Binding Protein, RNA Interference, RNA, Small Interfering, RNA-Binding Proteins, Reverse Transcriptase Polymerase Chain Reaction

Journal Title

EMBO J

Conference Name

Journal ISSN

0261-4189
1460-2075

Volume Title

34

Publisher

Wiley-VCH Verlag
Sponsorship
Wellcome Trust (092900/Z/10/Z)
Wellcome Trust (077877/Z/05/Z)
We thank Nejc Haberman (UCL) for assisting in the generation of the splicing maps and preparation of the iCLIP data. This work was supported by Wellcome Trust programme grants to CWJS (077877 and 092900), and by grants to EE and NB BIO2011-23920 and RNAREG (CSD2009-00080) from the Spanish Government and by the Sandra Ibarra Foundation for Cancer (FSI2013). JA was supported by a Boehringer Ingelheim Fonds studentship.