Final Report Summary - TRANSPOSOSTRESS (Impact of stress-induced transposon activities on human disease)
Transposable elements (TEs) are discrete segments of DNA that have the distinctive ability to move and replicate within genomes across the tree of life. The evolutionary success of TEs is powerfully underscored by the finding that about 60% of the human genome is TE-derived. TEs accumulate inactivating mutations over evolutionary time and give rise to a genomic fraction, often referred as ’junk DNA’. Indeed, the vast majority of these sequences is not essential to the host. Nevertheless, my research demonstrates that the impact of TEs was seriously underestimated.
The first objective of my research was to understand the interplay between TEs and their host. To model how a vertebrate-specific transposon senses and responds to cellular signals of the host organism, we studied molecular interactions of transposons with their host cellular mechanisms. My laboratory aimed at deciphering the basic mechanism, regulation and the consequence of transcriptional activation of (both transpositionally active or inactive) TEs. I investigated the impact and the potential risk of (epi)genetic destabilization inflicted by upregulation of human endogenous TEs or imprinted genes (sharing several features in regulation). The other objective of my research was to decipher evolutionary processes that “recycle” the inactive TEs, co-opt them for novel cellular function, such as TE-derived regulatory sequences or even novel genes. These studies do challenge the dogma that views TEs exclusively as parasites or “junk” DNA. In parallel, we set out to investigate the impact of TE-derived activities on the human genome in general and on disease mechanisms in particular, based on the central premise that some of these activities are stress-induced. The anticipated output of my research is a refined understanding of the interplay between TEs and host cells in mammals. Importantly, we also aimed at translating experience accumulated in TE research to genome manipulation technologies. Our goal was to integrate basic knowledge and its translation to establish a technology platform, including stem cell research, gene and cell therapy, transgenesis, cancer research and functional genomics. My team provides an effective bridge between basic research and clinical- as well as technological translation of a novel gene transfer and stem cell technologies. The TransposoSTRESS project has reached out both to clinics (e.g. clinical trials) and the biotech industry (e.g. MDCell, etc). Keywords of the projects are: Sleeping Beauty, PiggyBac, PGBD1, transposon, domestication/co-option, endogenous retrovirus, HERVH, HERVK, LINE-1, LAVA, Helitron, primate evolution, stress signalling, epigenetics, DNA repair, replication, cell cycle, protein stability, genome shuffling, HMGXB4, PCNA, chromatin remodelling, preimplantation embryogenesis, pluripotency, stem cells, cancer, neurodegenerative diseases, Alzheimer, macular degeneration, AMD, depression, preeclampsia, transgenesis, gene therapy, T cell, immunotherapy.
The first objective of my research was to understand the interplay between TEs and their host. To model how a vertebrate-specific transposon senses and responds to cellular signals of the host organism, we studied molecular interactions of transposons with their host cellular mechanisms. My laboratory aimed at deciphering the basic mechanism, regulation and the consequence of transcriptional activation of (both transpositionally active or inactive) TEs. I investigated the impact and the potential risk of (epi)genetic destabilization inflicted by upregulation of human endogenous TEs or imprinted genes (sharing several features in regulation). The other objective of my research was to decipher evolutionary processes that “recycle” the inactive TEs, co-opt them for novel cellular function, such as TE-derived regulatory sequences or even novel genes. These studies do challenge the dogma that views TEs exclusively as parasites or “junk” DNA. In parallel, we set out to investigate the impact of TE-derived activities on the human genome in general and on disease mechanisms in particular, based on the central premise that some of these activities are stress-induced. The anticipated output of my research is a refined understanding of the interplay between TEs and host cells in mammals. Importantly, we also aimed at translating experience accumulated in TE research to genome manipulation technologies. Our goal was to integrate basic knowledge and its translation to establish a technology platform, including stem cell research, gene and cell therapy, transgenesis, cancer research and functional genomics. My team provides an effective bridge between basic research and clinical- as well as technological translation of a novel gene transfer and stem cell technologies. The TransposoSTRESS project has reached out both to clinics (e.g. clinical trials) and the biotech industry (e.g. MDCell, etc). Keywords of the projects are: Sleeping Beauty, PiggyBac, PGBD1, transposon, domestication/co-option, endogenous retrovirus, HERVH, HERVK, LINE-1, LAVA, Helitron, primate evolution, stress signalling, epigenetics, DNA repair, replication, cell cycle, protein stability, genome shuffling, HMGXB4, PCNA, chromatin remodelling, preimplantation embryogenesis, pluripotency, stem cells, cancer, neurodegenerative diseases, Alzheimer, macular degeneration, AMD, depression, preeclampsia, transgenesis, gene therapy, T cell, immunotherapy.