The domestication of transposable elements and the genesis of human-specific transcription networks
Pr Didier TRONO
Laboratory of virology and genetics, EPFL, Lausanne, Switzerland
Monday, December 9th 2019 - 10 a.m.
- Auditorium, IGBMC
Hosted by Functional genomics and cancer, Ali HAMICHE
Transposable elements (TEs) contribute at least 50% of the human genome, and TE-embedded regulatory sequences (TEeRS) are major repositories of transcription factor (TF) binding sites. We previously contributed to demonstrate that KRAB- containing zinc finger proteins (KZFPs), which are encoded in the hundreds by the human genome, are key to the epigenetic silencing of TEs during early embryogenesis (Rowe et al. 2010, Nature 463, 237-240). While this was taken by many as the sign of an arms race between vertebrates and their TE invaders, we accumulated evidence that led us instead to propose that KZFPs are key to the domestication of TEeRS for the benefit of the host. Through a combination of phylogenetic and genomic studies, we presented a first set of evidence supporting this model by revealing that KZFPs exploit evolutionarily conserved fragments of transposable elements as regulatory platforms long after the arms race against these genetic invaders has ended, and appear to partner up with their TE targets to build largely species-restricted layers of epigenetic regulation (Imbeault et al. 2017, Nature 543, 550-554). We further revealed that evolutionarily recent KZFPs tame TEeRS shortly after embryonic genome activation (EGA) to facilitate their subsequent co-option in broadly active transcriptional networks (Pontis et al. 2019, Cell Stem Cell 24, 724-735). Based on these and other data, we suggested that TEs and their polydactyl controllers continuously feed genomes with intertwined sets of cis- and trans-acting regulators, thereby generating a genetic diversification that most often translates into mechanistic species-specificity in the conduct of processes otherwise conserved due to physiological and evolutionary constraints, but that in the brain and perhaps other organ systems, owing to a broader range of explorable phenotypes, it may result in phenotypic speciation. Our most recent data validate this general principle.