Upstream open reading frames (uORFs) are a common class of genetic elements and are widely recognized as constitutive regulatory elements that impinge on the translation of their associated physiological downstream open reading frames. Many mRNAs, particularly those encoding oncogenes, cytokines, growth factors etc., carry uORFs in their 5’ untranslated regions (UTRs) and polymorphisms that disrupt or create uORFs in human patients can result in or increase susceptibility to severe disorders such as hereditary thrombocythaemia, cancer, bipolar affective disorders, and Alzheimer’s disease. This underscores the broad significance of the uORF regulatory potential that potentially impacts on the protein output of half of the human transcripts.

Recently we could uncover a novel paradigm for the regulation of translation by demonstrating that a trans-acting factor – the RNA-binding protein Sxl – can modulate the activity of a uORF. Probing the generality of the underlying mechanism unraveled a network of co-regulated Drosophila mRNAs revealing a novel and possibly systematic principle for the regulation of protein synthesis.

Building on these findings we now set out to probe translation in the presence and absence of the regulatory protein on a global scale, making use of ribosomal profiling. This will enable us to directly monitor uORF translation under different physiological conditions with the aim to identify novel cases of protein-controlled uORFs, aiming for a broad understanding of uORF-mediated translational control and its implication in disease.