Control of Gene Expression by RNA Binding Protein Action on Alternative Translation Initiation Sites

Transcript levels do not faithfully predict protein levels, due to post-transcriptional regulation of gene expression mediated by RNA binding proteins (RBPs) and non-coding RNAs. We developed a multivariate linear regression model integrating RBP levels and predicted RBP-mRNA regulatory interactions from matched transcript and protein datasets. RBPs significantly improved the accuracy in predicting protein abundance of a portion of the total modeled mRNAs in three panels of tissues and cells and for different methods employed in the detection of mRNA and protein. The presence of upstream translation initiation sites (uTISs) at the mRNA 5’ untranslated regions was strongly associated with improvement in predictive accuracy. On the basis of these observations, we propose that the recently discovered widespread uTISs in the human genome can be a previously unappreciated substrate of translational control mediated by RBPs.Author Summary: Gene expression is a dynamic program by which the information stored in the genome is rendered functional by production and degradation of two types of macromolecules, RNAs and proteins. mRNAs are templates for proteins; therefore we expect correspondence between quantities of mRNAs and proteins. Genome-wide studies instead indicate a marked discrepancy between them, when considering their steady-state levels or their variations across different conditions. We employed linear regression approaches with paired mRNA/protein datasets in order to develop a model predicting the protein level of a gene from both the mRNA level and the protein levels of RBPs inferred to bind the mRNA untranslated regions. The results of our analyses restricted the utility of RBPs to improve accuracy of predicted protein abundance to a small fraction of the total modelled genes, and identified a novel association of the improvement induced by RBPs with the presence of upstream translation sites. This finding suggests a new avenue of experimental studies aimed at exploring the hypothesis that RBPs could influence protein abundance by changing the preference for certain translation initiation sites.