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RBM10 Deficiency Promotes Brain Metastasis by Modulating Sphingolipid Metabolism in an Animal Model of EGFR Mutation Lung Adenocarcinoma

ABSTRACT: Brain metastasis significantly contributes to the failure of targeted therapy in patients with EGFR-mutated lung adenocarcinoma (LUAD). Reduced expression of RBM10 is associated with brain metastasis in these patients. However, the mechanism by which RBM10 affects brain metastasis in EGFR-mutated LUAD remains unclear. Previous studies reveal that RBM10 mutations lead to decreased expression and deregulated splicing at a subset of junctions, primarily through exon skipping.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280915 | GEO | 2025/03/19

REPOSITORIES: GEO

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RBM10 Deficiency Promotes Brain Metastasis by Modulating Sphingolipid Metabolism in an Animal Model of EGFR Mutation Lung Adenocarcinoma

Project description:RBM10 Deficiency Promotes Brain Metastasis by Modulating Sphingolipid Metabolism in an Animal Model of EGFR Mutation Lung Adenocarcinoma

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A RRM1-ZnF RNA recognition module targets RBM10 to exonic sequences to promote exon exclusion

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Project description:RBM10 is an RNA binding protein that was identified as a component of spliceosome complex, suggesting its potential role in splicing regulation. However, the direct experimental evidence for this function has been lacking. Here we characterized in vivo RBM10-RNA interactions and investigated the role of RBM10 in splicing regulation at the global level. We observed significant RBM10-RNA interactions in the vicinity of splice sites and identified hundreds of splicing changes following perturbation of cellular RBM10 abundance. A RNA splicing map integrating the binding pattern and splicing profiles revealed a significant correlation between RBM10-enhanced exon skipping events and its binding close to the splicing sites of both upstream and downstream introns. Furthermore, we demonstrated the splicing defects in a patient carrying a RBM10 mutation. Overall, our data provided insights into the mechanistic model of RBM10-mediated splicing regulation and established genomic resources for future studies on its function in different pathophysiological contexts. We sequenced the mRNA of HEK293 cells and LCL cells, and we determined the RBM10 binding sites using PARCLIP in HEK293 cells. In total we sequenced four mRNA-Seq libraries for KD and two for OE in HEK293 cells; for each of these libraries, we also sequenced one control library. We also sequenced the mRNA of one patient LCL and two normal LCL libraries. Two replicates of PARCLIP sequencing were perfomed.

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