The role of epigenetic inheritance and 3D genome architecture in cellular state regulation and cancer

Giacomo Cavalli, PhD
Team Leader
Institute of Human Genetics (IGH)
French National Centre for Scientific Research (CNRS)
Montpellier, France

This conference is hosted by Jacques Drouin, PhD. This conference is part of the 2023-2024 IRCM conference calendar.

About this conference
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.

About Giacomo Cavalli
Giacomo Cavalli studied Biology at the University of Parma. In 1991, he moved to Zürich at the University of Science and Technology (ETH) to do his PhD, where he worked on chromatin structure and function in yeast with Dr. Fritz Thoma and Dr. Theo Koller. In 1995, he did his postdoc in the laboratory of Prof. Renato Paro at the University of Heidelberg. In December 1998, he moved to IGH in Montpellier, France, to set up a junior lab and stayed at IGH ever since. Giacomo Cavalli made seminal contributions in the field of epigenetics. Using the fruit fly Drosophila melanogaster, he discovered that epigenetic inheritance of new phenotypes can occur independently on changes of the DNA sequence. His lab also discovered that the three-dimensional organisation of chromosomes in the cell nucleus is a heritable trait that plays an important gene regulatory role. The Cavalli lab identified 3D structural chromosomal domains dubbed Topologically Associating Domains or TADs. Finally, the Cavalli lab has shown that cancer can be initiated by purely epigenetic mechanisms, as a consequence of a transient depletion of Polycomb components and in the absence of driver DNA mutations. Giacomo Cavalli has published 150 papers, cited over 24,000 times. He received numerous awards, including an EMBO membership, the CNRS silver medal, the Allianz Foundation prize, the Grand Prix 2020 of the Fondation pour la Recherche Médicale, the 2025 Griffuel Prize for cancer research of the ARC Foundation and three advanced investigator ERC grants. In 2022, he was named member of the French Academy of Sciences and he is an ISI Clarivate Highly Cited Researcher. He was director of the IGH Genome Dynamics department from 2007 to 2010 and IGH director from 2011 to 2014. He organized major international conferences and is appointed as members of several Institute- and Journal editorial boards.

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