Genomics of Chromosome Architecture and Dynamics in Single Cells

Informations projet

GoCADiSC

N° de convention de subvention: 694466

DOI

10.3030/694466

Projet clôturé

Date de signature de la CE 20 Mai 2016

Date de début 1 Mars 2017

Date de fin 31 Août 2022

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 497 125,00

Contribution de l’UE

€ 2 497 125,00

Coordonné par

STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Netherlands

Periodic Reporting for period 4 - GoCADiSC (Genomics of Chromosome Architecture and Dynamics in Single Cells)

Période du rapport: 2021-09-01 au 2022-08-31

Résumé du contexte et des objectifs généraux du projet

Each cell in our body contains 2 meters of DNA, packaged into a tiny space of about 0.01 mm in diameter, called the nucleus. How this packaging is achieved is still poorly understood. This packaging is in part guided by the attachment of certain DNA regions to fixed platforms. One of these is the nuclear lamina, a shell that lines the edge of the nucleus. Interestingly, the regions attached to the lamina (so-called LADs) mostly harbor genes that are inactive. This has led to the idea that the packaging of our DNA may help to control which genes are being used in a cell. Paradoxically, is has been found that the packaging of DNA is also somewhat "sloppy", as it changes over time and it varies a bit from cell to cell in a seemingly random manner. The goal of this project was to better understand the attachments of DNA to platforms such as the lamina. On the one hand, we aimed to study the cell-to-cell variation of these attachment in single cells, using new methods developed in our lab. On the other hand, we aimed to study how these attachments work: what is their molecular structure? For this we developed and applied new genomics methods. These tightly linked approaches have provided detailed understanding of the dynamic folding of DNA in individual human cells, and yielded new methods and data that can help other scientists to study this folding.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We have applied a method that can precisely map the contacts of DNA with the lamina, and studied in detail how these contacts change over time. We have also mapped the contacts of DNA with the nucleolus (another 'platform' in the nucleus), and identified a protein that controls these contacts. We have gained much insight into the way genes respond to the contacts with the lamina: some genes appear more sensitive than others. In addition, we identified dozens of proteins that are responsible for the repression of genes that are in contact with the lamina. Together, these results provide fundamental new insights into the spatial organisation of the genome.
In the course of this project, we have also developed powerful methodologies that can be applied to many questions in genome biology: 1. A highly multiplexed method to probe how broken DNA is repaired in different chromatin environments, including lamina-associated domains. 2. A powerful genome-wide method to fine-map sequences that drive gene expression, and to study the impact of human sequence variants on gene activity. This method has been the basis for a spin-out company and for the starting of a new large project aimed to better understand mutations in cancer genomes. 3. A method to systematically create sequence rearrangements in a genomic region of interest. With this approach we have identified stretches of DNA that are likely to serve as "anchor points" for contacts with the lamina. This method also forms the foundation for a new ERC Advanced project to study principles of gene regulation.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

These approaches have helped us to better understand the dynamic folding of DNA inside the nucleus, the underlying molecular mechanisms, and the impact on the regulation of genes and genome integrity. The newly developed technologies offer new powerful ways to study many aspects of genome biology. Long-term, this will contribute to a deep understanding of human genetics in health and disease.

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