Descripción del proyecto
Determinantes moleculares de la identidad celular
Las proteínas sufren modificaciones postraduccionales tras su síntesis, lo que les permite participar en diferentes procesos según el contexto celular. La sumoilación es una modificación que implica la adición de pequeños modificadores relacionados con la ubicuitina (SUMO, por sus siglas en inglés) a las proteínas, lo que modifica su función, estabilidad y localización. Pruebas recientes señalan que la sumoilación puede afectar a la plasticidad o la transición del destino celular. El proyecto SUMiDENTITY, financiado con fondos europeos, está diseñado sobre la base de que los SUMO, al actuar de forma específica sobre ciertos factores que se unen a la cromatina, regulan la expresión génica relacionada con el destino celular. El objetivo de sus investigadores es dilucidar el papel de los SUMO en el cambio del destino celular durante el desarrollo, así como tras una lesión.
Objetivo
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.
Ámbito científico
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Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
75654 Paris
Francia