Description du projet
Les déterminants moléculaires de l’identité cellulaire
Une fois synthétisées, les protéines subissent des modifications post-traductionnelles supplémentaires, qui leur permettent de contribuer à différents processus en fonction du contexte cellulaire. La sumoylation est une modification impliquant l’ajout de petits modificateurs apparentés à l’ubiquitine (SUMO) sur les protéines, affectant leur fonction, leur stabilité et leur localisation. Des observations récentes révèlent que la sumoylation peut affecter la transition du destin cellulaire ou sa plasticité. Le projet SUMiDENTITY, financé par l’UE, repose sur le principe selon lequel les SUMO, en ciblant certains facteurs qui se lient à la chromatine, régulent l’expression des gènes associés au destin cellulaire. Les chercheurs entendent découvrir le rôle des SUMO dans le changement du destin cellulaire au cours du développement et également suite à une blessure.
Objectif
The maintenance of cell identity and how it is subverted in disease are central questions in biology and medicine. The interplay between transcription factor and chromatin configurations plays a key role in maintaining cellular identity, yet how this interplay is regulated is poorly understood. Notably, the existence of possible general mechanisms underlying different cell-state specifications remains to be determined. We have recently uncovered evidence that sumoylation, which deposits a chromatin-associated mark (SUMO) that principally targets transcriptional regulators, acts as a general barrier to cell-fate transitions and enforces two distinctive chromatin types to safeguard somatic and pluripotent cell identities. The central paradigm for the proposed work is that SUMO functions as a general stabilizer of critical chromatin-bound determinants of cell identity and that the equilibrium between conjugating/deconjugating activities provides a general regulatory mechanism for their dynamic targeting to key chromosomal loci, thus actively contributing to cell-fate change. Focusing on reprogramming to pluripotency and transition to totipotent-like states, we propose to: 1) identify relevant locus-specific SUMO substrates/complexes in fibroblasts and ESCs, 2) define the role of SUMO in regulating their function and dynamics and, reciprocally, 3) explore the sumoylation/desumoylation balance that accompanies cell-fate change. A complementary effort seeks 4) to exploit these experimental approaches to study a paradigmatic pathophysiological process involving rapid cell-fate transitions: tissue repair following muscle injury. With a vision toward targeting this druggable pathway for regenerative medicine and cancer treatment, we expect these studies to integrate the gene regulatory roles of SUMO in resisting cell-fate change, thus opening up new avenues to the molecular mechanisms that specify cell identity during development and to how they are corrupted in disease.
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ERC-ADG - Advanced GrantInstitution d’accueil
75654 Paris
France