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

Descrizione del progetto

Caratterizzare il ruolo degli anelli gene-gene non paraloghi

Recenti ricerche sull’architettura genomica tridimensionale rivelano che geni specifici interagiscono fisicamente a grandi distanze genomiche; ciononostante, non è ancora chiaro se queste interazioni coordinino l’attività tra più geni. Sostenuto dal programma di azioni Marie Skłodowska-Curie, il progetto BRIDGE mira ad approfondire il modo in cui le interazioni fisiche tra geni distanti e non paraloghi (anelli gene-gene) influenzino i programmi trascrizionali e se si verifichino esclusivamente nei neuroni studiando a tal fine i contatti genici a lungo raggio e a coppie nei neuroni della mosca e in altri tipi di cellule, nonché verificando se coordinano la trascrizione e la funzione genica. I risultati ricavati dal progetto potrebbero portare alla luce nuovi meccanismi patologici nei mammiferi e spiegare come le strutture genomiche regolino più geni, aprendo la strada alla scoperta di terapie geniche avanzate.

Obiettivo

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.