MisterCHROM · Modelling sister chromatids cohesion
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-09-01 → 2024-08-31
- EU contribution
- €174,167
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Modelling sister chromatids cohesion
Over the past decade, collaborative efforts combining experimental and theoretical approaches have significantly advanced our understanding of the organization of individual chromosomes and their functional implications in various biological contexts. However, the cohesion process between pairs of replicated chromosomes has remained poorly understood, primarily due to the limitations of existing technologies in distinguishing their identical sequences. This gap has left critical questions regarding cohesion mechanisms and their biological impacts on other important cellular mechanisms unresolved. Daniel Gerlich’s lab at the hosting institution addressed this challenge by developing a sister-chromatid-sensitive Hi-C (scsHi-C) assay, enabling the first genome-wide analysis of the native conformation of sister chromatids in human replicated chromosomes. This project aimed to leverage the theoretical and computational expertise provided by Anton Goloborodko’s lab (the hosting lab), and the scsHi-C new experimental dataset provided by Gerlich's lab to establish a robust theoretical framework for modeling the structure and mechanisms of sister chromatid cohesion, its interaction with dynamic loop extrusion mechanisms, and its role in fundamental cellular processes such as gene expression and DNA repair. By integrating polymer simulations of chromosomes with analyses of genomic data, the Fellow successfully modeled for the first time how cohesive linkages are distributed along sister chromatids, leading to novel hypotheses regarding the mechanisms of cohesion establishment during replication. The Fellow discovered that the cohesive linkages tethering the two sister chromatids are asymmetrically misaligned. Specifically, these linkages connect non-homologous loci, leading to misalignment, and the connected loci consistently exhibit a lateral shift biased in one direction across the entire genome. This results in a skewed alignment of one sister chromatid relative to the other. These findings support a new hypothesis that the inherent asymmetry of the replication process is transferred to the cohesion mechanism during its establishment and is maintained, to some extent, until the onset of mitosis.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH · WienCoordinatorAustria
Links
Data: CORDIS, © European Union