An homeotic post-transcriptional network controlled by the RNA-binding protein RBMX

Post-transcriptional regulation (PTR) of gene expression is a powerful determinant of protein levels and cellular phenotypes. The 5’ and 3’ untranslated regions of the mRNA (UTRs) mediate this role through sequence and secondary structure elements bound by RNA-binding proteins (RBPs) and noncoding RNAs. While functional regions in the 3’UTRs have been extensively studied, the 5’UTRs are still relatively uncharacterized. To fill this gap, here we used a computational approach based on phylogenetic conservation to identify hyper-conserved elements in human 5’UTRs (5’HCEs). Our assumption, supported by the recovery of functionally characterized elements, was that 5’HCEs would represent evolutionarily stable and hence important PTR sites. We identified over 5000 short, clustered 5’HCEs occurring in approximately 10% of human protein-coding genes. Among these, homeotic genes were highly enriched. Indeed, 52 of the 258 characterized homeotic genes contained at least one 5’HCE, including members of all four Hox clusters and several other families. Homeotic genes are essential transcriptional regulators. They drive body plan and neuromuscular development, and the role of PTR in their expression is mostly unknown. By integrating computational and experimental approaches we then identified the RBMX RNA-binding protein as the initiator of a post-transcriptional cascade regulating many such homeotic genes. RBMX is known to control its targets by modulating transcript abundance and alternative splicing. Adding to that, we observed translational control as a novel mode of regulation by this RBP. This work thus establishes RBMX as a versatile master controller of homeotic genes and of the developmental processes they drive.