Uncovering mechanisms and organization underlying selective regulation of mRNA translation

The gene expression pathway includes transcription, mRNA translation, and protein degradation. Altered translation can rapidly modulate protein levels, without requiring changes in transcription, and can therefore efficiently control cellular responses. Despite evidence of key roles for transcript-selective modulation of translation, the extent and organization of translational control at a transcriptome-wide level is largely uncharted. Moreover, major cancer types appear to be under strong post-transcriptional regulation affecting metastasis and prognosis. TRANSLATOME aims to identify the organization and mechanisms underlying transcriptome-wide modulation of translation. First, I will explore and identify modules whose translation is consistently co-regulated across many cellular conditions, and therefore share common mechanisms, using network module identification. Dependencies between activities of translation modules, which are suggested from the preliminary data, will be studied in detail. This part will exploit polysome or ribosome profiling data from public repositories. Second, I will determine the mechanisms underlying translation modules and how their activities are orchestrated. This will be achieved by identifying RNA features driving the coordinated translation of mRNAs within modules, and how these – via encoded proteins – determine activities in key biological pathways. Finally, I will assess whether modules underlie translation patterns or subtypes of breast and glioblastoma tumours. This interdisciplinary approach requires molecular biology, bioinformatics, systems biology, algorithm development and applied statistics. TRANSLATOME will bring new insights into the transcriptome-wide organization of mRNA translation, which is pertinent to complex diseases. Particularly, I expect to elucidate how mRNA translation is altered in breast cancer and glioblastoma, paving the way for treatments aimed at reversing dysregulated translation programs in cancer.