Abstract

How RNA splicing events are targeted to the correct genomic locations in specific cellular contexts to generate context-specific transcript diversity remains very poorly understood. We show that a functionally conserved GA-rich DNA-binding transcription factor (TF), CLAMP, targets distinct RNA molecules in male and female cells to precisely regulate sex-specific splicing events through physical and functional interaction with RNA and RNA-binding proteins (RBPs). The prion-like domain of CLAMP (PrLD) and a stem-loop structure in the target RNA are essential for the CLAMP-RNA interaction. Moreover, the CLAMP PrLD domain regulates sex-specific splicing by modulating the dynamics of an hnRNPA2/B1 family protein that regulates alternative splicing. Thus, we demonstrate that a TF targets co-transcriptional splicing to the correct genomic locations by directly linking DNA binding sites to RNA targets and modulating the dynamics of RBP partners that drive alternative splicing.