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Laboratory of Translational Genomics

Research directions
Our work ranges from computational, systems-level representations of translation-centred networks to their mechanistic dissection in mammalian cells, and to the causative role of their derangement in cancer and neurodegeneration. Specific projects are:

  • Computational reconstruction of sequence-dependent translational control networks in whole genomes. Structural and sequence features clustered in the 5’ and 3’ UTRs of mRNAs dictate their fate in the cytoplasm, by the recruitment of RNA binding proteins and non-coding RNAs. By an in silico approach involving annotation of 5’ and 3’ untranslated regions of mRNAs from literature data and motif discovery algorithms we want to look at genes as specific combinations of signals for the mRNA metabolism, which can allow predictions on the shape of post-transcriptional networks. These predictions will be confirmed by benchmarking experiments in cultured cell models.
  • The translational network of the “poly(A)-derived superfamily” of RNA binding proteins. Using bioinformatics-based phylogenetic recontruction we are tracing the evolutive history of a group of paralogous genes conserved between invertebrates and vertebrates, and most likely derived by the ancestral poly(A)-binding protein. This group, including the PABP, ELAV, BRUNO and TIA protein families, represents the major cluster of orthologs among RRM-bearing RNA binding proteins in genomes, and is characterized by a variety of regulated and overlapping functions among which sequence-dependent translational control. By a combination of computational and systems-based approaches including RIP-chip and microarray-based polysomal profiling, we are starting to define the function of this macromolecular networking machine in dictating the translational status of the array of bound mRNAs.
  • Sequence-dependent translational control derangement in cancer onset and progression. Recent findings point out to the deregulation of translational control by altered signalling pathways as a leading cause of cancer onset and progression. We are conducting a systematic analysis of the involvement of some RNA binding proteins and ribosomal proteins, the major final targets of these pathways, in solid tumors.
  • Activity imbalance of ELAV proteins in high risk neuroblastoma. Neuroblastoma is a neural crest-derived tumor which represents the major cause of death in infants. A particularly aggressive form of this cancer is cytogenetically characterized by two recurrent lesions, monoallelic loss of region in the p arm of chromosome 1 and amplification of the MYCN oncogene. Both these alterations can be causally related to alterations in the activity of members of the ELAV family of RNA binding proteins, physiologically involved in the transition from neural stem cells to differentiating neurons. We hypothesize that ELAV protein alteration of activity is a determinant of neuroblastoma progression, and a possible therapeutic target.
  • Translational control of synaptic plasticity in memory and memory-impairing disorders by the ELAV network. Previous studies by the group leader involved for the first time post-transcriptional control of gene expression in cognition, demonstrating activation of ELAV proteins as a necessary process for spatial memory encoding. Preliminary data are now demostrating lesions in the ELAV network as a possible determinant of late-onset Alzheimer disease, by affecting the non-amylodogenic pathway in neurons.