Chromatin and Cell Biology

 Giacomo CAVALLI

 IGH - UMR 9004

 141, rue de la Cardonille, 34396 Montpellier

Phone: +33 4 34 35 99 70

Email: giacomo.cavalli@igh.cnrs.fr

Website

In the cell nucleus DNA is folded into chromatin, an essential component in the regulation of genome function (Sexton and Cavalli, 2015). Polycomb group (PcG) and trithorax group (trxG) proteins are key regulators of the expression of major developmental genes. PcG proteins are able to silence gene expression (Schuettengruber et al. 2007), while trxG proteins counteract gene silencing in the appropriate cells (Schuettengruber et al. 2011). These proteins function to maintain the memory of gene regulatory states through mitotic divisions of the different cell lineages. They accomplish this function by binding to specific regulatory elements called Polycomb/trithorax response elements (PREs) and modifying the flanking chromatin. Importantly, PcG proteins regulate the organization of their target genes in the three-dimensional space of the nucleus, and this regulatory function is involved in the maintenance of cellular memory.

Research in the Cavalli lab has highlighted the importance of nuclear architecture and affirmed the concept of 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. (Bantignies et al. 2003; Bantignies et al. 2011; Sexton et al. 2012). Furthermore the work showed that long-distance chromosomal interactions depend not only on PcG proteins, but also on components of the RNAi machinery (Grimaud et al. 2006).

On the molecular level, the research objective is to understand how Polycomb and trithorax proteins are recruited to DNA(Dejardin et al. 2005). At the systems level, the lab was among the first to carry out large-scale mappings of the distribution of PcG proteins and we carried out the first high-resolution microscopy genome-wide screen for components modifying the nuclear organization of Polycomb components. Finally, the lab showed that PcG proteins regulate target genes involved in the cell cycle (Martinez et al. 2006, Iovino et al. 2013), and one PcG gene, polyhomeotic, is a tumor suppressor gene that controls cell proliferation via regulation of Notch signaling (Martinez et al. 2009).

Keywords: Chromosome, Polycomb, Trithorax, 3D Genome, Nuclear organization, Drosophila, Mouse, Human

Main publications

• Bonev, B., Mendelson Cohen, N., Szabo, Q., Fritsch, L., Papadopoulos, G., Lubling, Y., Xu, X., Lv, X., Hugnot, J.-P., Tanay, A., and Cavalli, G. (2017). Multi-scale 3D genome rewiring during mouse neural development. Cell 171, 557-572.e24.
• Ciabrelli, F., Comoglio, F. Fellous, S., Bonev, B., Ninova, M., Szabo, Q., Xuéreb, A., Klopp, C., Aravin, A. Paro, R., Bantignies, F., and Cavalli, G. Stable Polycomb-dependent transgenerational inheritance of chromatin states in Drosophila (2017). Nature Genet, doi:10.1038/ng.3848.
• Schuettengruber, B., Bourbon, H., Di Croce, L., and Cavalli, G. (2017). Genome Regulation by Polycomb and Trithorax: 70 years and counting. Cell 171, 34-57.
• Loubiere, V., Delest, A., Thoma, A., Bonev, B., Schuettengruber, B., Sati, S., Martinez, AM., and Cavalli, G. (2016). Coordinate redeployment of PRC1 proteins suppresses tumor formation during Drosophila development. Nature Genet, 48, 1436-1442, doi:10.1038/ng.3671.
• Bonev, B., and Cavalli, G. (2016). Organization and function of the 3D genome. Nature Reviews Genet. Oct 14;17(11):661-678. doi: 10.1038/nrg.2016.112.
• Sexton, T., and Cavalli, G. (2015). The role of chromosome domains in shaping the functional genome. Cell, 160, 1049-1059.
• Gonzalez, I., Mateos-Langerak, J., Thomas, A., Cheutin, T., and Cavalli, G. Identification of new regulators of three dimensional Polycomb organization by a microscopy-based genome-wide RNAi screen (2014). Mol Cell 54, 485-99, pii: S1097-2765(14)00209-3. doi: 10.1016/j.molcel.2014.03.004.
• Iovino, N., Ciabrelli, F., and Cavalli, G. (2013). PRC2 controls Drosophila oocyte cell fate by repressing cell cycle genes. Dev. Cell 26, 431-439.
• Sexton, T., Yaffe, E., Kenigsberg, E., Bantignies, F., Leblanc, B., Hoichman, M., Parrinello, H., Tanay, A., and Cavalli, G. (2012). Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458-472.
• Schuettengruber, B, Martinez, AM, Iovino, N., Cavalli, G. Trithorax group proteins : switching genes on and keeping them active. Nature Reviews Mol Cell Biol. (2011) 12, 799-814.