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

Abstract

© 2015 The Authors. Published under the terms of the CC BY 4.0 license.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. Synopsis Matrin3 is a nuclear matrix protein that was recently linked to neurodegeneration. This study finds Matrin3 to be a splicing repressor that modulates hundreds of alternative splice events, offering possible insight on disease onset. Nuclear matrix protein Matrin3 uses a GILGPPP motif to dock onto the RRM2 domain of splice regulator PTB. Transcriptome-wide profiling shows changes in hundreds of alternative splicing events (ASE) upon Matrin3 knockdown; only a subset of these are also regulated by PTB. Unlike other splicing regulators, Matrin3 binds to extended regions within and around repressed exons. Matrin3 requires its RRMs and the GILGPPP motif to regulate splicing of both PTB-dependent and PTB-independent ASEs, suggesting possible crosstalk with other RRM-containing splice factors. The finding that Matrin3 plays a role in controlling alternative splicing may help understand the etiology of Matrin3-associated pathologies. Matrin3 is a nuclear matrix protein that was recently linked to neurodegeneration. This study finds Matrin3 to be a splicing repressor that modulates hundreds of alternative splice events, offering possible insight on disease onset.