Alternative polyadenylation (APA) has been implicated in a variety of developmental and disease processes. A particularly dramatic form of APA occurs in the developing nervous system of flies and mammals, whereby approximately 200 developmental genes undergo coordinate 3’UTR extension. The RNA-binding protein ELAV inhibits RNA processing at proximal polyadenylation sites, thereby fostering the formation of these exceptionally long 3’UTRs.
We found that paused Pol II promotes recruitment of ELAV to its target genes. Replacing promoters of extended genes with heterologous promoters blocks normal 3’ extension in the nervous system, while extension-associated promoters can induce 3’ extension in ectopic tissues expressing ELAV. Computational analyses show that promoter regions of extended genes tend to contain paused Pol II and associated cis-regulatory elements such as GAGA. ChIP-Seq assays identify ELAV in the promoter regions of extended genes. We provide the first evidence for a regulatory link between promoter-proximal pausing and APA.
Neuron-specific APA is conserved in humans. 3’UTR extensions are enriched in conserved regulatory motifs, indicating that extended mRNAs play a specific role in the regulatory networks that drive neural development and brain function. Our functional genetics studies reveal that deleting 3'UTR extensions in Drosophila results in diverse phenotypes such as neurodegeneration and life span lengthening.