A conserved 3'UTR short motif regulates gene expression in vertebrates

The messenger RNA (mRNA) 3' untranslated region (3'UTR) contains important regulatory sequences, including upstream sequence elements (USEs), which regulate gene expression. One well-characterised USE in the 3'UTR of the Drosophila polo gene affects adult fly phenotypes when disrupted. We have now identified a highly conserved sequence within this USE (DplUSE) in the 3'UTR of several vertebrate genes, including in zebrafish, mouse, and human genomes and show that DplUSE enhances gene expression in human cells and zebrafish embryos. We show that, in humans, DplUSE-containing genes are associated with congenital disease processes, and that disruption of DplUSE function impairs zebrafish development. We also found that HuR/ELAVL1, hnRNPC, and PTBP1/hnRNPI bind to DplUSE RNA and are required for its activity in a human cell line, suggesting a highly conserved mechanism across distantly related species. Our results indicate that PTBP1 has a global function in alternative polyadenylation, activating the selection of distal polyA sites and repressing intronic polyadenylation in DplUSE-containing genes while hnRNPC and HuR modulate their expression. Additionally, we found that a colon cancer-associated SNP in the POU2AF2/C11orf53 3'UTR creates an ectopic DplUSE site, increasing gene expression in zebrafish gut cells and in a human cell line. We have therefore identified a short 3'UTR motif present in diverse vertebrate genes that controls their expression through conserved RBPs interactions and is implicated in human disease.