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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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3799496 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation.

Wang Yongbo Y Gogol-Döring Andreas A Hu Hao H Fröhler Sebastian S Ma Yunxia Y Jens Marvin M Maaskola Jonas J Murakawa Yasuhiro Y Quedenau Claudia C Landthaler Markus M Kalscheuer Vera V Wieczorek Dagmar D Wang Yang Y Hu Yuhui Y Chen Wei W

EMBO molecular medicine 20130822 9

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 ...[more]

PMID: 24000153

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Project description:Spinal cord injury (SCI) causes damage to the spinal cord owing to trauma or disease and myelinated fiber tracts that transmit sensation and motor signals to and from the brain. Circular RNAs (circRNAs) are a recently discovered class of regulatory molecules, and their roles in SCI are still unknown. circRNA_014301 was indicated to be differentially expressed in the spinal cord at the site of SCI in a rat model. To analyze the role of circRNA_014301 in SCI, we exposed rat adrenal pheochromocytoma PC12 cells were exposed to increasing concentrations of lipopolysaccharide (LPS) and to construct a PC12 cell inflammatory model. Cell Counting Kit-8 assay was used to analyze cell viability. Reverse transcription-quantitative PCR and ELISA were used to detect the expression of inflammatory factors (IL-1β, IL-6 and TNF-α). Annexin V-FITC/PI double staining was employed to detect cell apoptosis, and western blotting was performed to detect the expression of apoptotic proteins (Bax/Bcl-2/cleaved caspase-3) and NF-κB. The results demonstrated that LPS induced inflammation in PC12 cells as evidenced by the reduced cell proliferation and enhanced expression of inflammatory and apoptotic factors under increasing LPS concentrations. Western blotting analyses indicated that circRNA_014301 induced the expression of p-NF-κB/NF-κB, Bax and cleaved caspase-3, and decreased the expression of Bcl-2 following LPS-induced inflammation, and this apoptosis-promoting effect was relieved by small interfering-RNA-mediated knockdown of circRNA_014301. Thus, circRNA_014301 silencing alleviated apoptosis and inflammation in PC12 cells. SCI is invariably associated with spinal cord inflammation, and LPS was used to stimulate apoptosis and inflammatory injury in PC12 cells, and create a cell model of SCI. By promoting PC12 cell apoptosis under inflammatory conditions, it was indicated that circRNA_014301 may suppress SCI. Therefore, circRNA_014301 may represent a potential target for SCI diagnosis and therapy.

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Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation.

Publications

Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation.

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