Functional dissection of X-linked regulatory DNA: unravelling the impact of genome topology on transcriptional regulation

Description du projet

L’interconnexion entre la topologie chromosomique et la régulation transcriptionnelle

Un nombre croissant de preuves indique que les génomes des mammifères sont organisés en sous‑domaines topologiquement distincts qui interagissent les uns avec les autres et partagent le paysage de régulation. Bien que la perturbation de ces domaines ait été associée à la maladie, on ignore s’ils incarnent une conséquence de l’activité transcriptionnelle. Les scientifiques du projet eXcape3D, financé par l’UE, utiliseront l’inactivation du chromosome X (XCI) comme système modèle pour identifier les éléments de régulation impliqués dans la formation des sous‑domaines chromosomiques. Le projet fournira des informations importantes sur la topologie du génome et le rôle du génome non codant dans la régulation des gènes.

Objectif

Mammalian genomes are structurally organized into sub-chromosomal self-interacting domains called topologically associating domains (TADs). Functionally, genes embedded within the same TAD appear to be co-regulated by their shared regulatory landscapes, suggesting the tendency of the genome to be divided into discrete regulatory domains. Although disrupting TAD boundaries has been shown to result in aberrant patterns of gene expression, whether TAD organisation is cause or consequence of transcriptional activity remains largely unknown, as well as the regulatory elements that direct TAD formation and long-range chromatin interactions within TADs. This project aims to define the exact functional link between genome topology and transcriptional regulation by exploiting the mammalian dosage compensation mechanism X-Chromosome Inactivation (XCI) as a model system. First, I will identify the combination of regulatory elements that allow a subset of X-linked genes to resist the transcriptional silencing of one entire X chromosome in female cells. Then, I will characterise their functional and structural relevance by combining advanced epigenetic tools for the manipulation of complex regulatory networks with transcriptomic analysis and chromosome conformation capture, an innovative method that allows to define the 3D structure of chromosomes within the nucleus. This project represents a unique opportunity to enhance our understanding of genome topology, providing valuable insights into the roles of the non-coding genome in gene regulation. Considering my personal professional background, and the outstanding level of scientific excellence of the host institution, this project promises a great potential of radically advancing the field and, in addition, will provide the European Research Area with a highly-qualified expert scientist who has the technical and complementary skills to successfully lead a European research team.