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Noncoding and Translational Modulation of Gene Expression and Epigenetic Changes

Final Report Summary - TRANSLATE (Noncoding and Translational Modulation of Gene Expression and Epigenetic Changes)

The goal of our proposal was to make one step forward in the identification of molecular markers and therapeutic targets that are important in the human immune response. In human cells, the conversion of DNA into mRNA, known as transcription, represents the first layer of gene expression. The second layer of regulation of gene expression is represented by translation. It is often neglected that many biomarkers identified at the transcriptional level are not confirmed at the protein level due to translational control. Before of our study, almost all attempts at identifying the biomarkers of the immune response were grounded on the analysis of transcribed genes. In our study, we implemented a series of novel approaches that focused on the identification of biomarkers and therapeutic targets that are regulated at the translational level.
In order to achieve our goal, we have focused on the metabolic changes that accompany T cell activation. In particular, in the transition from a human naïve T cell to an effector T cell, cells exit from a quiescence status and acquire a highly dynamic stage. The transition must be at the same time rapid and very specific, in order to avoid delayed responses or over-activation. Due to the rapidity of this transition, we hypothesized that it was regulated mostly at the translational level. Accordingly, we have identified a network of genes regulated at the translational level that account for the T cell response. For instance, we have shown that the translation of pre-existing mRNAs enables the rapid metabolic switch required for activation of naive T cells. As a consequence of our finding, we now hypothesize that therapeutic targeting of specific translational steps is more efficient than traditional strategies hitting downstream events.