Description du projet
Vue d’ensemble de l’importance d’une inactivation transcriptionnelle lors de la division cellulaire
Les cellules qui subissent une division mitotique cessent presque toute activité transcriptionnelle. Cependant, on ignore si ce processus est indispensable pour une séparation précise du chromosome ou si c’est uniquement une conséquence de la division cellulaire. Le projet ChromoSilence, financé par l’UE, a pour objectif de découvrir l’importance de l’inactivation transcriptionnelle mitotique (MTI pour «mitotic transcriptional inactivation») lors de la division nucléaire. Pour cela, des chercheurs utiliseront des approches précises de perturbation qui leur permettront d’étudier le processus cellulaire selon une résolution temporelle sans précédent. Le projet devrait dévoiler les mécanismes et les acteurs qui interviennent dans la MTI et devrait déterminer son impact sur les processus de développement et de spécification cellulaire.
Objectif
Coordination between major cellular functions, such as transcription and proliferation, is critical to ensure cell survival. It has long been recognised that while in mitosis, cells switch-off most of their transcriptional activity. While Mitotic Transcriptional Inactivation (MTI) is entrenched as a dogma in cell biology, its functional consequences have been difficult to pin down, as manipulating MTI in the context of a developing organism has been difficult until now. My lab has pioneered the use of acute perturbation approaches to dissect cellular process with unprecedented temporal resolution, which hold the prospect of surpassing current limitations on the identification and manipulation of multiple MTI layers. Using these novel approaches, ChromoSilence aims to test the hypothesis that MTI is a vital process for proper genome partitioning and transcriptional control. We will focus our analysis on chromosome-based events, that we propose as key contributors for MTI regulation, and test how classic chromosome assembly factors impact on mitotic transcriptional shutdown. In parallel, and supported by strong preliminary observations for a putative candidate, we will identify and reveal the function of novel players involved in chromosome-based mechanisms to drive MTI. New knowledge on the MTI mechanisms will be used to develop tools to uncover the role of this transcriptional shutdown in the fidelity of nuclear division and thereby identify novel routes to maintenance of genome stability. We will additionally uncover how the transcriptional silencing during mitosis may impact on maintenance of transcriptional programs in various developmental contexts. Collectively, ChromoSilence will reveal that MTI is not a by-product of passage through mitosis but instead an essential process for accurate chromosome segregation, maintenance of cell identity and organism development.
Champ scientifique
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
1067-001 LISBOA
Portugal