title: Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation.
abstract: 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.
authors.affiliation: Laboratory for Novel Sequencing Technology, Functional and Medical Genomics, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Wang
authors.forename: Andreas
authors.initials: A
authors.lastname: Gogol-Döring
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fröhler
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Ma
authors.forename: Marvin
authors.initials: M
authors.lastname: Jens
authors.forename: Jonas
authors.initials: J
authors.lastname: Maaskola
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Murakawa
authors.forename: Claudia
authors.initials: C
authors.lastname: Quedenau
authors.forename: Markus
authors.initials: M
authors.lastname: Landthaler
authors.forename: Vera
authors.initials: V
authors.lastname: Kalscheuer
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D017398:Alternative Splicing; D003025:Clubfoot / Q000235:genetics*; D005786:Gene Expression Regulation; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D010855:Pierre Robin Syndrome / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: C512260:RBM10 protein, human; D016601:RNA-Binding Proteins
keywords: RBM10; alternative splicing; mechanistic model