Mechanism and regulation of Hu family RNA binding proteins during neural alternative polyadenylation

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PROJECT ABSTRACT 3' untranslated regions (3' UTRs) are the hubs of post-transcriptional regulation, and contain the majority of binding sites for regulatory factors such as miRNAs and RNA binding proteins (RBPs). Moreover, it has recently become appreciated that most genes do not express a single 3' UTR, but instead express multiple 3' UTR isoforms through a process known as alternative polyadenylation (APA). Since APA can be deployed to coordinately shift the 3' UTR profiles of large cohorts of genes according to tissue identity, environmental condition, or disease status, APA can broadly affect the post- transcriptional landscape and profoundly impact gene expression programs. Nevertheless, very little remains known about the underlying mechanisms of how global APA programs are enacted. In ongoing work, we identify conserved, redundant roles for Hu family neural RBPs in driving a broad program of neural 3' UTR lengthening in both Drosophila and mammalian nervous system. Here, we will use molecular genetic assays and genomewide analyses to elucidate the mechanism for neural Hu proteins in conferring neural 3' UTR extensions. Since neural Hu factors have such powerful capacity to remodel the transcriptome, it may follow that they are under strict control. Indeed, we have also found that neural Hu genes in both Drosophila and mammals are subject to unexpectedly complex and strong post-transcriptional suppression outside of the nervous system. We have developed new genetic models to study these regulatory mechanisms and their phenotypic impacts, which may reveal new roles for these factors in developmental patterning and also have tangible implications for a class of human disease that is caused by misexpression of neural Hu proteins outside of the brain. Overall, this work will reveal new perspectives on the deployment of the distinctive neural post-transcriptional landscape and its in vivo biological importance.