The role of Polycomb proteins and 3D genome architecture in epigenetic inheritance and cancer
Giacomo Cavalli
Institute of Human Genetics - Université de Montpellier, France
Anne-Marie Martinez1,2 and Giacomo Cavalli1,2
1 Institute of Human Genetics, CNRS, 34396 Montpellier Cedex 5, France
2 University of Montpellier, Montpellier, France
Epigenetic components regulate many biological phenomena during development and normal physiology. When dysregulated, epigenetic components can also accompany or drive diseases. One main class of epigenetic components are Polycomb group proteins. Originally, Polycomb proteins were shown to silence gene expression. We found that this function involves the regulation of 3D chromosome folding and we found that Polycomb components can induce the formation of long-distance interactions or chromatin loops that may play instructive roles in gene regulation as well as serve as scaffolding elements that contribute to enhancer-promoter specificity. Perturbation of Polycomb components is involved in human cancer and leads to tumorigenesis in flies. Surprisingly, even upon a transient depletion followed by restoration of the full Polycomb compendium, epithelial cells lose their normal differentiated fate, continue proliferating and establish aggressive tumors, demonstrating that cancer can have a fully epigenetic origin. Investigation of chromatin perturbation in mouse ES cells and gastruloids shows that they can record chromatin changes and that this results in cellular memory of the perturbation states. The implication of these data will be discussed.
Acknowledgements
This work was supported by the European Research Council Advanced Investigator grant (3DEpi), by the “Fondation ARC pour la recherche sur le cancer”, by the “Fondation pour la recherche médicale” (FRM), by INSERM and the ITMO Cancer (MMTT project), by the INCa, the E-RARE IMPACT grant under the ERA-NET Cofund Horizon 2020 scheme, by the MSD-Avenir foundation and by the CNRS.