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Genomics of Chromosome Architecture and Dynamics in Single Cells

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

Reporting period: 2021-09-01 to 2022-08-31

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.
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.
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.