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.
Highlights
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
We demonstrated the splicing defects in a patient carrying an RBM10 mutation, which could be explained by disrupted function of RBM10 in splicing regulation
Functional investigation of an in-frame deletion of RBM10 identified in a patient with TARP syndrome Nonsense and frame‐shift mutations in RBM10 have been identified to be causative for TARP syndrome (Johnston et al, 2010)
Summary
Its closest paralogue RBM5, a putative tumour suppressor of lung and other cancers (Sutherland et al, 2005), has been shown to regulate AS of apoptosis related genes, Fas receptor and c‐FLIP, resulting in isoforms with antagonistic functions in controlling programmed cell death (Bonnal et al, 2008) All these observations would suggest the potential role of RBM10 in pre‐mRNA splicing regulation, it remains unclear whether and how RBM10 could regulate splicing. Multiple truncating and missense somatic mutations were detected in lung adenocarcinomas (Imielinski et al, 2012) These findings implicated the important role of RBM10, but whether its potential function in splicing regulation is involved in these different pathological contexts has not been explored. Our transcriptome‐wide analysis of binding pattern and RBM10 splicing profile allows the illustration of the molecular mechanism underlying RBM10 regulated AS
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