Overlapping Activities of ELAV/Hu Family RNA Binding Proteins Specify the Extended Neuronal 3′ UTR Landscape in Drosophila

• DOI: 10.1016/j.molcel.2020.09.007
• Publication Date: 2020-10-01T14:39:18Z
• Authors: Lu Wei; Seungjae Lee; Sonali Majumdar; Binglong Zhang; Piero Sanfilippo; Brian Joseph; Pedro Miura; Matthias Soller; Eric C. Lai
• Keywords: Cell Nucleus; Neurons; 0303 health sciences; Amino Acid Motifs; Cell Line; Alternative Splicing; 03 medical and health sciences; Drosophila melanogaster; ELAV Proteins; Larva; Mutation; Animals; Drosophila Proteins; Protein Isoforms; RNA, Messenger; Poly A; 3' Untranslated Regions

The tissue-specific deployment of highly extended neural 3' UTR isoforms, generated by alternative polyadenylation (APA), is a broad and conserved feature of metazoan genomes. However, the factors and mechanisms that control neural APA isoforms are not well understood. Here, we show that three ELAV/Hu RNA binding proteins (Elav, Rbp9, and Fne) have similar capacities to induce a lengthened 3' UTR landscape in an ectopic setting. These factors promote accumulation of chromatin-associated, 3' UTR-extended, nascent transcripts, through inhibition of proximal polyadenylation site (PAS) usage. Notably, Elav represses an unannotated splice isoform of fne, switching the normally cytoplasmic Fne toward the nucleus in elav mutants. We use genomic profiling to reveal strong and broad loss of neural APA in elav/fne double mutant CNS, the first genetic background to largely abrogate this distinct APA signature. Overall, we demonstrate how regulatory interplay and functionally overlapping activities of neural ELAV/Hu RBPs drives the neural APA landscape.