About the lab

The genome is more than a linear string of genes. Genes organize in chromosomal domains that are characterized by one of relatively few different types of chromatin, either repressive or activating. In the 3D space, each of the elements in one domain makes frequent contacts with other elements in the same domain. These entities have been called physical- or topologically associated- domains (TADs). Individual TADs form contacts with other TADs, in order to build ordered 3D architectures that are called chromosome compartiments and territories.
Our lab uses Drosophila and mammalian cell models with the goal to understand the regulatory principles of genome architecture and their impact on gene expression during development, cell differentiaon and in cancer.

Featured projects (1)

Project
We would like to understand the role of Polycomb proteins in Cancer. We have previously shown that these components behave as tumour suppressors in the Drosophila model system and previous literature has linked mutations or dysregulation of Polycomb proteins in human cancer. We would like to understand the mechanism of tumour suppression in flies and whether some of it applies to humans. We hope that this research can elucidate mechanisms of cell differentiation as well as pave the way to the identification of novel prognostic biomarkers and to new therapeutic avenues.

Featured research (10)

Increasing evidence indicates that non-DNA sequence-based epigenetic information can be inherited across several generations in organisms ranging from yeast to plants to humans. This raises the possibility of heritable ‘epimutations’ contributing to heritable phenotypic variation and thus to evolution. Recent work has shed light on both the signals that underpin these epimutations, including DNA methylation, histone modifications and non-coding RNAs, and the mechanisms by which they are transmitted across generations at the molecular level. These mechanisms can vary greatly among species and have a more limited effect in mammals than in plants and other animal species. Nevertheless, common principles are emerging, with transmission occurring either via direct replicative mechanisms or indirect reconstruction of the signal in subsequent generations. As these processes become clearer we continue to improve our understanding of the distinctive features and relative contribution of DNA sequence and epigenetic variation to heritable differences in phenotype.
https://www.youtube.com/watch?v=Pl44JjA--2k&t=8s Synopsis of the YouTube video: this short video recapitulates our current understanding of genome organization in the three-dimensional space of the cell nucleus, starting from nucleosomes, which wrap 146 base pairs of DNA, all the way to entire chromosome territories that may contain hundreds of million base pairs of DNA sequence. In-between these two extremes, the hierarchical folding of the chromatin fiber into “nucleosome clutches”, “chromatin nanodomains or CNDs”, “Topologically Associating Domains or TADs” (including their mechanism of formation via loop-extrusion) and the “A and B compartments” are presented. We include below references that support and supplement what is described in our video. We stress that some of the mechanisms involved in 3D genome organization are still debated in this research field. We also include below additional videos on the subject. Enjoy the video!
Cohesin loop extrusion facilitates precise gene expression by continuously driving promoters to sample all enhancers located within the same topologically-associated domain (TAD). However, many TADs contain multiple genes with divergent expression patterns, thereby indicating additional forces further refine how enhancer activities are utilised. Here, we unravel the mechanisms enabling a new gene, Rex1, to emerge with divergent expression within the ancient Fat1 TAD in placental mammals. We show that such divergent expression is not determined by a strict enhancer-promoter compatibility code, intra-TAD position or nuclear envelope-attachment. Instead, TAD-restructuring in embryonic stem cells (ESCs) separates Rex1 and Fat1 with distinct proximal enhancers that independently drive their expression. By contrast, in later embryonic tissues, DNA methylation renders the inactive Rex1 promoter profoundly unresponsive to Fat1 enhancers within the intact TAD. Combined, these features adapted an ancient regulatory landscape during evolution to support two entirely independent Rex1 and Fat1 expression programs. Thus, rather than operating only as rigid blocks of co-regulated genes, TAD-regulatory landscapes can orchestrate complex divergent expression patterns in evolution. HIGHLIGHTS New genes can emerge in evolution without taking on the expression pattern of their surrounding pre-existing TAD. Compartmentalisation can restructure seemingly evolutionarily stable TADs to control a promoter’s access to enhancers. Lamina-associated domains neither prevent transcriptional activation nor enhancer-promoter communication. Repression rather than promoter-specificity refines when genes respond to promiscuous enhancer activities in specific tissues.
During animal evolution, de novo emergence and modifications of pre-existing transcriptional enhancers have contributed to biological innovations, by implementing gene regulatory networks. The Drosophila melanogaster bric-a-brac ( bab ) complex, comprising the tandem paralogous genes bab1 - 2 , provides a paradigm to address how enhancers contribute and co-evolve to regulate jointly or differentially duplicated genes. We previously characterized an intergenic enhancer (named LAE) governing bab2 expression in leg and antennal tissues. We show here that LAE activity also regulates bab1 . CRISPR/Cas9-mediated LAE excision reveals its critical role for bab2 -specific expression along the proximo-distal leg axis, likely through paralog-specific interaction with the bab2 gene promoter. Furthermore, LAE appears involved but not strictly required for bab1 - 2 co-expression in leg tissues. Phenotypic rescue experiments, chromatin features and a gene reporter assay reveal a large “pleiotropic” bab1 enhancer (termed BER) including a series of cis -regulatory elements active in the leg, antennal, wing, haltere and gonadal tissues. Phylogenomics analyses indicate that (i) bab2 originates from bab1 duplication within the Muscomorpha sublineage, (ii) LAE and bab1 promoter sequences have been evolutionarily-fixed early on within the Brachycera lineage, while (iii) BER elements have been conserved more recently among muscomorphans. Lastly, we identified conserved binding sites for transcription factors known or prone to regulate directly the paralogous bab genes in diverse developmental contexts. This work provides new insights on enhancers, particularly about their emergence, maintenance and functional diversification during evolution. Author summary Gene duplications and transcriptional enhancer emergence/modifications are thought having greatly contributed to phenotypic innovations during animal evolution. However, how enhancers regulate distinctly gene duplicates and are evolutionary-fixed remain largely unknown. The Drosophila bric-a-brac locus, comprising the tandemly-duplicated genes bab1 - 2 , provides a good paradigm to address these issues. The twin bab genes are co-expressed in many tissues. In this study, genetic analyses show a partial co-regulation of both genes in the developing legs depending on tissue-specific transcription factors known to bind a single enhancer. Genome editing and gene reporter assays further show that this shared enhancer is also required for bab2 -specific expression. Our results also reveal the existence of partly-redundant regulatory functions of a large pleiotropic enhancer which contributes to co-regulate the bab genes in distal leg tissues. Phylogenomics analyses indicate that the Drosophila bab locus originates from duplication of a dipteran bab1 -related gene, which occurred within the Brachycera (true flies) lineage. bab enhancer and promoter sequences have been differentially-conserved among Diptera suborders. This work illuminates how transcriptional enhancers from tandem gene duplicates (i) differentially interact with distinct cognate promoters and (ii) undergo distinct evolutionary changes to diversifying their respective tissue-specific gene expression pattern.

Lab head

Giacomo Cavalli
Department
  • Institut de Génétique Humaine
About Giacomo Cavalli
  • Giacomo Cavalli currently works at the Institut de Génétique Humaine, French National Centre for Scientific Research. Giacomo does research in Molecular Biology, Developmental Biology and Cancer Research. His lab focus is on 3D Genome folding and on the function of Polycomb and Trithorax proteins in epigenetic inheritance. Their current project is 'Epigenetic regulation of development.

Members (12)

Bernd Schuettengruber
  • Université de Montpellier
Frédéric Bantignies
  • French National Centre for Scientific Research
Gonzalo Sabaris
  • The Institute of Human Genetics
Thierry Cheutin
  • Institut de Génétique Humaine
Ivana Jerković
  • Institut de Génétique Humaine
Anne-Marie Martinez
  • French National Centre for Scientific Research
Lauriane Fritsch
  • The Institute of Human Genetics
Maximilian Fitz-James
  • Institut de Génétique Humaine
Michael Szalay
Michael Szalay
  • Not confirmed yet
Victoria Parreno
Victoria Parreno
  • Not confirmed yet
Hadrien Reboul
Hadrien Reboul
  • Not confirmed yet
Ana Maria Popmihaylova
Ana Maria Popmihaylova
  • Not confirmed yet