Coelho Miguel B, Attig Jan, Bellora Nicolás, König Julian, Hallegger Martina, Kayikci Melis, Eyras Eduardo, Ule Jernej, Smith Christopher W J
Department of Biochemistry, University of Cambridge, Cambridge, UK.
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK MRC-Laboratory of Molecular Biology, Cambridge, UK.
EMBO J. 2015 Mar 4;34(5):653-68. doi: 10.15252/embj.201489852. Epub 2015 Jan 19.
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.
Matrin3是一种与RNA和DNA结合的核基质蛋白，已发现其与神经和肌肉退行性疾病有关。人们已经提出了Matrin3的一些可能功能，但尚未明确证明其在RNA代谢中具有广泛作用。我们通过其与剪接调节因子PTB的第二个RRM结构域的相互作用鉴定出了Matrin3。通过RNAi敲低、转录组分析和iCLIP相结合的方法，我们发现Matrin3是数百种可变剪接事件的调节因子，主要作为剪接抑制因子起作用，只有一小部分靶向事件由PTB共同调节。与其他剪接调节因子不同，Matrin3与被抑制外显子及其侧翼内含子内的一个延伸区域结合，没有明确界定的峰值。Matrin3这一明确分子功能的鉴定应有助于阐明肌萎缩侧索硬化症（ALS）和其他由Matrin3突变引起的疾病的分子病理学。
