RNA regulons in Hox 5' UTRs confer ribosome specificity to gene regulation.

Abstract

Emerging evidence suggests a regulatory function of the ribosome in directing how the genome is translated in time and space. However, how this regulation is encoded in mRNA sequence remains largely unknown. Here we uncover unique RNA regulons embedded in Homeobox (Hox) 5′UTRs that confer ribosome-mediated control of gene expression. These structured RNA elements, resembling viral Internal Ribosome Entry Sites (IRESes), are found in subsets of Hox mRNAs. They facilitate ribosome recruitment and require Ribosomal Protein L38 for their activity. Despite numerous layers of Hox gene regulation, these IRES elements are essential for converting Hox transcripts into proteins to pattern the mammalian body plan. This specialized mode of IRES-dependent translation is enabled by a regulatory element, the Translational Inhibitory Element (TIE), which blocks cap-dependent translation of these transcripts. Together, these data uncover a new paradigm for ribosome-mediated control of gene expression and organismal development.