Descrizione del progetto
Fattori molecolari determinanti dell’identità cellulare
In seguito alla sintesi, le proteine subiscono ulteriori modifiche post-traslazionali, che consentono loro di contribuire a diversi processi a seconda del contesto cellulare. La sumoilazione è una modifica che comporta l’aggiunta di piccoli modificatori correlati all’ubiquitina (SUMO, Small Ubiquitin-related Modifier) sulle proteine, condizionandone la funzione, la stabilità e la localizzazione. Alcune prove recenti indicano che la sumoilazione potrebbe influire sulla transizione o sulla plasticità del destino delle cellule. Il progetto SUMiDENTITY, finanziato dall’UE, è concepito sulla base della logica secondo cui i SUMO, nel prendere di mira determinati fattori che si legano alla cromatina, regolano l’espressione genica associata al destino cellulare. I ricercatori intendono svelare il ruolo dei SUMO nel cambiamento del destino cellulare durante lo sviluppo e in seguito a lesioni.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
75654 Paris
Francia