Modelling sister chromatids cohesion

Projektbeschreibung

Neue Modelle zur Entschlüsselung der Dynamik von Schwesterchromatiden

Als Schwesterchromatid-Kohäsion wird der Vorgang bezeichnet, durch den Schwesterchromatiden während bestimmter Phasen des Zellzyklus gepaart und zusammengehalten werden. Ihre Organisation und ihre Rolle bei Zellfunktionen sind jedoch noch nicht geklärt, da es gegenwärtig an angemessenen Verfahren fehlt, um zwischen ihren identischen Sequenzen zu unterscheiden. Das im Rahmen der Marie-Skłodowska-Curie-Maßnahmen finanzierte Projekt MisterCHROM wird sich ein jüngst entwickeltes und erfolgreich erprobtes Verfahren zunutze machen, das es erstmals ermöglicht, eine genomweite Analyse der Interaktion von Schwesterchromatiden durchzuführen. Insbesondere bezweckt das Projekt die Entwicklung theoretischer Modelle, um die komplexen Schwesterchromatid-sensiblen Kontaktmuster und die Mechanismen hinter der Bildung und Aufrechterhaltung der Schwesterchromatid-Kohäsion besser zu verstehen.

Ziel

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.