Modelling sister chromatids cohesion

Descripción del proyecto

Nuevos modelos para esclarecer la dinámica de las cromátides hermanas

La cohesión de las cromátides hermanas se refiere al proceso mediante el cual se emparejan y se mantienen juntas durante ciertas fases del ciclo celular. Su organización y contribución a las funciones celulares se habían mostrado esquivas por la inexistencia de técnicas adecuadas capaces de distinguir sus secuencias idénticas. El equipo del proyecto MisterCHROM, financiado por las Acciones Marie Skłodowska-Curie, aprovechará una reciente y exitosa técnica que logró, por primera vez, un análisis de genoma completo de las interacciones de las cromátides hermanas. En particular, tiene previsto desarrollar modelos teóricos para comprender mejor los complejos patrones de contacto sensibles de las cromátides hermanas y los mecanismos subyacentes a la formación y mantenimiento de la cohesión entre cromátides hermanas.

Objetivo

The proposed project aims at modeling the structure and mechanisms of sister chromatids cohesion, and how it coordinates with intra-chromatid organization to shape replicated human chromosomes and support fundamental biological mechanisms. Indeed, sister chromatids organisation and its contribution to cellular functions remained elusive due to the lack of appropriate techniques able to distinguish the identical sequences of sister chromatids. The recent development of sister-chromatid-sensitive Hi-C (scsHi-C) technique by Gerlich's group at the host institution enables, for the first time, genome-wide analysis of sister chromatids interactions. These data now require theoretical models based on general physical principles to understand the complex scsHi-C contact patterns and the mechanisms underlying the formation and maintenance of sister chromatids cohesion. I will use coarse-grained polymer simulations and analytical calculations to: (i) unravel the structural and statistical features of sister chromatids organisation, e.g. how cohesive linkages distribute on the genome and the relative impact on sister chromatids conformation and alignment; (ii) understand the interplay of cohesion with dynamic intra-chromatid loops and TADs formation; (iii) predict outcomes of system perturbations on chromosome conformations and functional implications in processes such as gene expression, mitotic chromosome organisation, and DNA repair. Because the topology of sister chromatids is uncharted territory, whatever new knowledge is gained by the modeling approach proposed in this highly innovative study will constitute important contributions to long-standing open questions in the field, and will outline pathways towards new directions to pursue in future research. Given the relevance for various physiological processes, the outcomes of this project will be highly relevant for biologists from various fields, as well as biophysicist. The opportunity and the timing are thus unique.