BRIDGE: Uncovering the biological relevance of non-paralogous gene-gene loops in coordinating transcription and function across neurons and other cell types

Description du projet

Caractériser le rôle des boucles gène-gène non paralogues

De récentes recherches sur l’architecture 3D du génome révèlent que certains gènes interagissent physiquement sur de grandes distances génomiques. Nous ignorons toutefois si ces interactions coordonnent l’activité de plusieurs gènes. Soutenu par le programme Actions Marie Skłodowska-Curie, le projet BRIDGE va étudier l’influence des interactions physiques entre des gènes distants et non paralogues (boucles gène-gène) sur les programmes transcriptionnels et si ces interactions se produisent exclusivement dans les neurones. Il étudiera les contacts gènes-gènes par paires à longue portée dans les neurones de la mouche et d’autres types de cellules, afin de vérifier s’ils coordonnent la transcription et la fonction des gènes. Les résultats pourraient révéler de nouveaux mécanismes pathologiques chez les mammifères et expliquer comment les structures génomiques régulent plusieurs gènes, ouvrant ainsi la voie à de nouvelles thérapies géniques de pointe.

Objectif

Gene transcription is tightly controlled by regulatory elements in the genome. While most act locally, distant regulatory elements are increasingly recognized as key contributors to gene control, revising our fundamental understanding of how regulatory interactions are organized in genomes. Recent three-dimensional (3D) genome folding studies showed that some genes form specific, long-range physical contacts with other gene loci. However, whether such contacts coordinate multi-gene activity remains unknown.

My BRIDGE (Biological Regulation of Interacting Distant GEnes) project investigates ultra-long-range, pairwise gene contacts recently discovered in fly neurons. These gene pairs are not known to function together but engage in highly specific and conserved contacts. Using the simplicity of these contacts and their suitability for in vivo manipulation, this project will test whether these distant gene contacts coordinate gene transcription and function in neurons and other cell types.

Through genome engineering, chromatin imaging, genomics and genetic assays, I will disrupt or rewire these contacts (WP1-3) and analyze their biological impact. WP4 will explore whether these contacts extend beyond neurons by comparing 3D genome organization across four differentiated cell types from all germ layers.

BRIDGE will determine whether long-range gene tethering is a neuron-specific or broader regulatory mechanism. It may also uncover novel functional synergies between mammalian disease-relevant homologs of the studied genes. More broadly, BRIDGE will deepen our understanding of how genome organization enables multi-gene regulation, with long-term implications for developing gene therapies targeting gene networks. It will also provide interdisciplinary training and career development to support my transition to independent research at the interface of 3D genomics and gene regulation.