Bioinformatics detection of modulators controlling splicing factor‐dependent intron retention in the human brain. Issue 11 (10th May 2022)

• Record Type: Journal Article
• Authors: Chen, Steven X.; Simpson, Ed; Reiter, Jill L.; Liu, Yunlong
• Other Names: Scott Stuart A. guestEditor.; Wang Kai guestEditor.; Spinner Nancy B. guestEditor.
• Is Part Of: Human mutation. Volume 43:Issue 11(2022)
• Page Start: 1629
• Page End: 1641
• Publication Date: 2022-05-10
• Subjects: alternative splicing regulation -- bioinformatics -- brain -- intron retention -- Mendelian randomization -- SRSF1; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24379
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Alternative RNA splicing is an important means of genetic control and transcriptome diversity. However, when alternative splicing events are studied independently, coordinated splicing modulated by common factors is often not recognized. As a result, the molecular mechanisms of how splicing regulators promote or repress splice site recognition in a context‐dependent manner are not well understood. The functional coupling between multiple gene regulatory layers suggests that splicing is modulated by additional genetic or epigenetic components. Here, we developed a bioinformatics approach to identify causal modulators of splicing activity based on the variation of gene expression in large RNA sequencing datasets. We applied this approach in a neurological context with hundreds of dorsolateral prefrontal cortex samples. Our model is strengthened with the incorporation of genetic variants to impute gene expression in a Mendelian randomization‐based approach. We identified novel modulators of the splicing factor SRSF1, including UIMC1 and the long noncoding RNA CBR3‐AS1, that function over dozens of SRSF1 intron retention splicing targets. This strategy can be widely used to identify modulators of RNA‐binding proteins involved in tissue‐specific alternative splicing.