Alternative RNA splicing is an important means of genetic control and transcriptome diversity. Alternative splicing events are frequently studied independently, and coordinated splicing controlled by common factors is often overlooked: The molecular mechanisms by which splicing regulators promote or repress specific pre-mRNA processing are still not yet well understood. It is well known that splicing factors can regulate splicing in a context-dependent manner, and the search for modulation of splicing factor activity via direct or indirect mechanisms is a worthwhile pursuit towards explaining context-dependent activity. We hypothesized that the combined analysis of hundreds of consortium RNA-seq datasets could identify trans-acting “modulators” whose expression is correlated with differential effects of a splicing factor on its target splice events in mRNAs. We first tested a genome-wide approach to identify relationships between RNA-binding proteins and their inferred modulators in kidney cancer. We then applied a more targeted approach to identify novel modulators of splicing factor SRSF1 function over dozens of its intron retention splicing targets in a neurological context using hundreds of dorsolateral prefrontal cortex samples. Our hypothesized model was further strengthened with the incorporation of genetic variants to impute gene expression in a Mendelian randomization-based approach. The modulators of intron retention splicing we identified may be associated with risk variants linked to Alzheimer’s Disease, among other neurological disorders, to explain disease-causing splicing mechanisms. Our strategy can be widely used to identify modulators of RNA-binding proteins involved in tissue-specific alternative splicing.

Indiana University-Purdue University Indianapolis (IUPUI)