3D map of the Drosophila genome
Giacomo Cavalli is investigating heredity and gene regulation laws beyond DNA sequence. He and his lab discovered that the 3D structure of chromosomes can be heritable and that it contributes to genome regulation. Furthermore, they provided the first high-resolution description of the principles of genome folding in animals. Finally, the Cavalli lab showed that PcG proteins regulate cell proliferation and have tumor suppression activity in flies, a model system which harbors 75% of the genes known to cause a disease in humans.
We are more than our DNA! In the last couple of decades it has become clear that chromosomal components such as histones, regulatory proteins and noncoding RNAs contribute to regulate all aspects of DNA function and contribute to heredity. Our lab has mainly focused on the analysis of proteins of the Polycomb and Trithorax groups: key regulators of the expression of major developmental genes that coordinate the processes of cell diff erentiation and cell proliferation.
Polycomb proteins are able to silence gene expression, while Trithorax proteins counteract gene silencing in the appropriate cells. We have studied how Polycomb and Trithorax proteins are recruited to DNA, we published the first large-scale mapping of the distribution of Polycomb group proteins along Drosophila chromosomes and we demonstrated that polyhomeotic, a Polycomb group gene, is a tumor suppressor that controls cell proliferation by regulating Notch signaling.
A distinctive feature of these proteins is their ability to maintain the memory of gene regulatory states through successive mitotic divisions in the different cell lineages. We showed that the regulation of chromosome architecture by these proteins contributes the transgenerational epigenetic inheritance of chromatin states by revealing that the transmission of this mitotic and meiotic cellular memory can bring into play long-distance chromosomal interactions in the three-dimensional space of the cell nucleus. We then extended the analysis of chromosome architecture by analyzing at genomewide scale the contacts made by each locus with all other chromosome loci in the genome. From this study, we deduced the principles governing chromosome organization and the functional implications of regulation of genome architecture.
We recently identified an exquisitely specific function of the PRC2 polycomb complex in the determination of the Drosophila oocyte. Inactivation of PRC2 genes results in the loss of silencing of cell cycle genes, which induces a fate switch whereby the oocyte transdetermines into a nurse-like cell. This research has uncovered a critically important function for a subset of Polycomb proteins in the transmission of life to subsequent generations.
Giacomo Cavalli’s work thus allowed to identify new roles for Polycomb genes, from tumor suppression to life transmission to subsequent generations. His work also uncovered for the first time the general principles governing the 3D organization of a metozoan genome.
• 1994, PhD in Natural Sciences, ETH Zürich, Switzerland. Fritz Thomas’ lab, chromatin and transcription in yeast.
• 1995-1998 Postdoc at the University of Heidelberg, Germany. Renato Paro’s Lab, Polycomb proteins and fly development
• Honour team, Fondation Association pour la Recherche sur le Cancer, 2013
• Allianz Foundation Research Prize, 2012
• Silver Medal of the CNRS, 2011
• Award of a grant for the Laboratory of Excellence EpiGenMed, 2011
• Advanced Investigator Grant of the European Research Council (ERC), 2008
Results summarized in several broad audience newspapers “Researchers discover new mechanism of epigenetic inheritance in fruit flies”
Oct 2009, Nat Genetics