European Commission logo
English English
CORDIS - EU research results
CORDIS

Topological interactions as functional regulators of the eukaryotic genome: moving beyond intramolecular looping

Project description

Role of the topological interactions in the chromosome biology

Topological interactions between distant DNA segments are fundamental for the eukaryotic genome function. Hi-C is a chromosome conformation capture technique that provides insights into the 3D organisation of the genome. The recently developed sister-chromatid-sensitive Hi-C (scsHi-C) technique demonstrated the potential to elucidate the mechanisms by which sister-chromatid conformation controls DNA repair, gene regulation, and the segregation of mitotic chromosomes. The EU-funded TopoGenomics project aims to develop next-generation scsHi-C technology to obtain high-resolution genome-wide conformation maps of sister chromatids and establish a machine learning-based computational framework to detect topological structures in sister chromatids. The project will advance understanding of the topological interaction of sister chromatids to support the maintenance, expression and segregation of eukaryotic genomes.

Objective

Topological interactions between distant DNA segments play fundamental roles in the function of eukaryotic genomes. While tremendous progress has been made in understanding the molecular mechanisms shaping intramolecular chromosome loop structures, limitations in our ability to distinguish specific chromosome conformations between paired molecules has hindered research into the role of interactions across separate chromosomal DNA molecules. Our recent development of an approach allowing analysis of contacts between sister chromatids now provides an opportunity for research into topological interactions to enter a new phase. Initial analyses with sister chromatid-sensitive Hi-C (scsHi-C) have indicated enormous potential to elucidate the mechanisms by which sister-chromatid conformation controls processes as varied as DNA repair, gene regulation and the segregation of mitotic chromosomes. To fulfil this potential, we will now develop next-generation scsHi-C technology to generate high-resolution genome-wide conformation maps of sister chromatids, along with the establishment of a machine learning-based computational framework to systematically detect topological structures in sister chromatids. This will be complemented with an imaging-based super-resolution approach to trace sister-chromatid fibers in thousands of individual cells. These core advances will allow us to map distinct sister-chromatid contact domains and identify associated molecular signatures, understand how loop-extruding and cohesive cohesin interact to shape replicated chromosomes, and determine how epigenetic modifications control pairing between sister chromatids. Together, these developments will allow us to make key advances in understanding a fundamental yet largely neglected aspect of chromosome biology—how replicated sister chromatids topologically interact to support maintenance, expression, and segregation of eukaryotic genomes.

Host institution

INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Net EU contribution
€ 2 792 500,00
Address
DR BOHRGASSE 3
1030 Wien
Austria

See on map

Region
Ostösterreich Wien Wien
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Links
Total cost
€ 2 792 500,00

Beneficiaries (1)