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Genomics of Chromosome Architecture and Dynamics in Single Cells

Periodic Reporting for period 3 - GoCADiSC (Genomics of Chromosome Architecture and Dynamics in Single Cells)

Reporting period: 2020-03-01 to 2021-08-31

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 lead 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 is to better understand the attachments of DNA to platforms such as the lamina. On the one hand, we will study the cell-to-cell variation of these attachment in single cells, using new methods developed in our lab. On the other hand, we aim to study how these attachments work: what is their molecular structure? For this we use new genetic methods.
These tightly linked approaches will provide detailed understanding of the dynamic folding of DNA in individual human cells, and yield new methods and data that can help other scientists to study these questions more effectively.
We have developed a method that can precisely map the contacts of DNA with the lamina, and found that these contacts change over time. We have also gained much insight into the way genes respond to these contacts: some genes appear more sensitive than others. In addition, we have set up a method to identify proteins that are responsible for shutting down genes that are in contact with the lamina. Finally, we have begun to develop a method to locally unfold DNA inside the cell, in order to better understand the importance of this folding.
Together, these approaches will help us to understand the dynamic folding of DNA inside the nucleus, the underlying molecular mechanisms, and the impact on the regulation of genes in a single cell. Long-term, our understanding of the folding of DNA will contribute to insights in human genetics in health and disease.