Deciphering the Regulatory Sequences Involved in Translation Regulation During Stress

Protein translation is known to be highly regulated in response to stress in mammals, often providing immediate and effective change in protein levels and thereby resulting in effective activation of adaptation and survival programs. Sequences within the 5’UTRs of mRNAs play a major role in translation regulation. Such 5′UTR sequences are thought to encode a variety of cis-regulatory elements, including upstream AUGs, upstream ORFs, internal ribosome entry sites, RNA-binding protein binding sites, and secondary structures. We aim to systematically quantify the effects of 5’UTR determinants on translation regulation and identify RNA features within these sequences that regulate translation in response to stress conditions, as well as in steady-state conditions, in mammalian cells, on a global scale.
First, we started by exploring the effects of proteotoxic stresses on cellular transcription and translation in a transcriptome-wide fashion. Preliminary analysis of Translation efficiency (TE) was performed in order to identify genes that are regulated preferentially at the level of translation. Computational analyses further characterized groups of genes that are regulated stress-specifically, or across several stress conditions. In addition, using flow cytometry, next generation sequencing and bioinformatics tools, we are screening thousands of 5’UTR sequences to examine their effects on different patterns of translation regulation in response to stress in human and mouse cells. Integrating these two approaches, we aim to derive biological insights on the roles of different cis-regulatory elements in translation regulation in stress and steady-state conditions.