Final Report Summary - RETROGENOMICS (Mechanisms of retrotransposition in humans and consequences on cancer genomic plasticity.)
DNA molecules carry the genetic information of living organisms by encoding genes and regulatory features, which control how and when genes should be expressed. One of the most surprising outcomes of large-scale genome projects has been to reveal the extent of repetitive DNA without known function in the genome of all living organisms, from bacteria to humans. Among these repeats, jumping genes, pieces of DNA able to self-replicate through cut-and-paste or copy-and-paste mechanisms are the most abundant. These jumps can eventually lead to new genetic diseases in humans by altering gene structure or regulation. Until recently such events were considered as extremely rare and the vast majority of these repeats were considered as molecular fossils of our past evolution. The advances of sequencing technologies have dramatically changed this view. Not only they participate to the genetic diversity of the modern human population, but also they profoundly affect our physiology by jumping in the brain or during oncogenesis. It is presently unknown how cells keep them under control to limit their damaging effects and why they become activated in some circumstances or pathologies. Our work aims at deciphering how jumping genes interact with and are controlled by their cellular host, and to understand how these mechanisms are unleashed during tumorigenesis. First, we have identified a broad range of cellular RNAs bound to and regulated by the molecular machinery encoded by jumping genes. Second, we have been able to reconstitute in a test tube the initial steps of jumping gene replication, revealing that their insertion in the genome is not random. Finally, we have been able to identify which individual jumping gene copies are reactivated in a panel of cancer cells, providing insights in the mechanism of their regulation. This was achieved through an integrative genomic approach, which combines a dedicated technique, developed in our laboratory in the course of the project, and able to identify the chromosomal location of each jumping gene throughout the genome, with big data mining of public databases. To support this work, we have also built and publicly released the most comprehensive database of jumping gene insertions in humans identified in healthy or pathological human samples (euL1db). Our work has advanced our knowledge of the mechanisms leading to jumping gene activation and how this process impacts the dynamics of the human genome.