Institute of Human Genetics, Montpellier, CNRS, France
3D map of the Drosophila genome
We are more than the sequence of our DNA. The Cavalli lab has contributed significantly to this simple but fundamental achievement of five decades of research following the description of the DNA double helix. Indeed, in addition to inheritance of characters depending strictly on the DNA sequence, there is another form of heritability, called “epigenetic inheritance”. This inheritance involves protein and RNA components that, by interacting with DNA molecules folded in the cell nucleus to form chromosomes, can produce alternative functions and maintain them through cell division into subsequent generations.
Giacomo Cavalli has a long-standing interest in the regulation of epigenetic inheritance. His lab is studying the role of the 3D organization of our genome, with a specific focus on the role of two groups of epigenetic components called Polycomb and Trithorax proteins. They define cell identity via the regulation of many other critical developmental genes. Polycomb and Trithorax factors maintain, respectively, repressed and active transcriptional states of their targets by binding to regulatory DNA regions and modulating the chromatin surrounding them.
Using the fruit fly Drosophila melanogaster, Giacomo Cavalli discovered that epigenetic inheritance of new phenotypes can occur independently on changes of the DNA sequence. The very same DNA can be driven into opposite functional states that could then be transmitted to multiple subsequent generations thanks to the action of Polycomb and Trithorax proteins.
The second fundamental discovery made in the Cavalli lab is that the three dimensional organisation of chromosome in the cell nucleus is a heritable trait that can play an important gene regulatory role. Polycomb bound chromatin regions can interact in the cell nucleus even when they are on different chromosomes, or at distant locations on the same chromosome. These contacts can be inhherited thanks to the action of Polycomb proteins. Thus, if this action is perturbed, the three dimensional contacts are lost even in the presence of all the necessary DNA sequences. These heritable three-dimensional chromosomal contacts can regulate gene expression and may thus be important modulators of cellular differentiation. In particular, the Cavalli lab optimized a method, called Hi-C, that allowed the high-resolution mapping of chromosome contacts and to reveal the main architectural principles of chromosome folding in Drosophila melanogaster. The data showed that the entire genome is linearly partitioned into well-demarcated physical domains (that have been dubbed topologically associating domains or TADs). Chromosomal contacts are hierarchically organized between domains. Global modeling of contact density and clustering of domains showed that inactive domains are condensed and confined to their chromosomal territories, whereas active domains reach out of the territory to form remote intra- and interchromosomal contacts. Moreover, the Cavalli lab systematically identified specific long-range intrachromosomal contacts between Polycomb-repressed domains. Further studies of the Cavalli lab have dissected genome folding dynamics during neural differentiation in mouse and during cell senescence in human. Furthermore, the lab demonstrated that TADs can be further subdivided into smaller domains called chromosome nanodomains (CNDs), which are a universal folding principle of eukaryotic chromatin.
The third main discovery of the Cavalli lab is that Polycomb proteins suppress tumor formation in Drosophila. Polycomb-dependent tumors induce activation of the Notch and Jak-STAT signaling pathways and these are essential for tumor progression. Furthermore, only a subset of the Polycomb genes is involved in cancer, whereas other members do not participate. The Cavalli lab showed that tumor suppression by Polycomb involves not only silencing of canonical target genes, but also activation of differentiation genes that involves binding of PRC1 Polycomb complexes to their promoters and enhancers. This binding is conserved in mammalian cells, suggesting that this work may open new avenues for human cancer research.
The importance of Giacomo Cavalli’s work has been acknowledged by various grant awards and prizes, as well as nominations in important panels at grant agencies, international meeting boards and scientific journals. To understand his role in this field, it is sufficient to google “Polycomb”, and his lab website will steadily appear first or second of more than 150,000 other webpages.
In summary, Giacomo Cavalli has been one of the world leading investigators in the field of epigenetics and has established an excellently funded and staffed lab that has every chance to contributing further important discoveries in the coming years.
• 1991 - 1994, PhD, ETH Zürich, Fritz Thoma lab, chromatin and transcription
• 1995-1998 Postdoc at the University of Heidelberg, Germany. Renato Paro’s Lab, Drosophila epigenetics
• 2008 - Grand Prix of the French Academy of Sciences. Full description : "Académie des Sciences – Institut de France : Grand prix quadriennal Paul Doisteau - Émile Blutet"
• 2008 - Election to EMBO Member
• 2009 - Advanced Investigator Grant of the European Research Council (ERC).
• 2011 - Silver Medal of the CNRS
• 2012 - Allianz Foundation Research Prize, Grand Prix of the French Academy of Sciences
• 2013 - Prize « Equipe à l’Honneur de Association pour la Recherche sur le Cancer (ARC) »
• 2017 – Second Advanced Investigator Grant of the European Research Council (ERC).
• 2020 – Nominated chair of the LS2 Coordinator Grant panel of the ERC
• 2020 – Grand Prix of the Fondation pour la Recherche Médicale
One hour broadcast on France Culture, the scientific method
Results summarized in several broad audience newspapers “Researchers discover new mechanism of epigenetic inheritance in fruit flies”