These authors contributed equally to this work.
Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation
Article first published online: 22 AUG 2013
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 9, pages 1431–1442, September 2013
How to Cite
Wang, Y., Gogol-Döring, A., Hu, H., Fröhler, S., Ma, Y., Jens, M., Maaskola, J., Murakawa, Y., Quedenau, C., Landthaler, M., Kalscheuer, V., Wieczorek, D., Wang, Y., Hu, Y. and Chen, W. (2013), Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation. EMBO Mol Med, 5: 1431–1442. doi: 10.1002/emmm.201302663
- Issue published online: 3 SEP 2013
- Article first published online: 22 AUG 2013
- Manuscript Accepted: 12 JUL 2013
- Manuscript Revised: 6 JUL 2013
- Manuscript Received: 20 FEB 2013
- Federal Ministry for Education and Research (BMBF)
- Berlin Institute of Medical Systems Biology (BIMSB) (315362A, 315362C)
- China Scholarship Council (CSC)
- GENCODYS (241995) in the European Union Framework Programme 7
- alternative splicing;
- mechanistic model
RBM10 encodes an RNA binding protein. Mutations in RBM10 are known to cause multiple congenital anomaly syndrome in male humans, the TARP syndrome. However, the molecular function of RBM10 is unknown. Here we used PAR-CLIP to identify thousands of binding sites of RBM10 and observed significant RBM10–RNA interactions in the vicinity of splice sites. Computational analyses of binding sites as well as loss-of-function and gain-of-function experiments provided evidence for the function of RBM10 in regulating exon skipping and suggested an underlying mechanistic model, which could be subsequently validated by minigene experiments. Furthermore, we demonstrated the splicing defects in a patient carrying an RBM10 mutation, which could be explained by disrupted function of RBM10 in splicing regulation. Overall, our study established RBM10 as an important regulator of alternative splicing, presented a mechanistic model for RBM10-mediated splicing regulation and provided a molecular link to understanding a human congenital disorder.