A matter of shape: how genome form influences function – PhD defense Pim Rullens

Our body consists of 37 trillion cells. Nearly every one of these cells carries identical DNA, also known as the genome. However, despite their identical genome, every cell is unique. Our bodies contain a variety of different cell types, such as muscle cells, nerve cells and skin cells. How is it possible that cells with the same genetic information look and function so differently? The three-dimensional form of the genome in a cell plays an important role in how the cell uses it. In his PhD, Pim set out to investigate exactly how genome form influences function.

New tool, new discoveries

Cells contain several proteins that can regulate the three-dimensional form of the genome. When Pim started his PhD, there were no tools to study in single cells how these molecules interact. Part of his project was to develop a method that could do exactly that.

Using this tool, he then discovered that large regions of the X chromosome relocate within the cell nucleus during X-inactivation, a process that happens in early development in female mammals. During this process, one of the two X chromosomes is inactivated, because only the genetic information of one is needed for development. “We found that relocation of these large regions of the inactive X chromosome is tightly linked with its epigenetic state,” Pim says.

The ‘epigenetic state’ refers to the molecular tags on the chromosome that tell a cell what parts of the DNA need to be active and inactive. If you think of DNA as a cookbook, you could think of the epigenetic state of DNA as bookmarks and sticky notes, telling the cell which recipes to use and which to ignore, without changing the recipe itself. Pim’s discovery of the relocation of the X chromosome thus gives new insights into the mechanism behind X-inactivation. “This finding may also open up new ways to analyze X-linked diseases, which are conditions caused by genetic changes on the X chromosome,” Pim says.

DNA on the move

Pim also discovered that certain very long genes, essential for brain development, change their position within the cell nucleus during the development of the cerebral cortex, the part of the brain to which mammals owe their higher cognitive abilities. This repositioning is regulated by a specific protein, MeCP2. The gene that encodes for this protein is mutated in the neurodevelopmental Rett syndrome. This finding may therefore shine new light on the molecular mechanisms underlying Rett syndrome, suggesting that an abnormality in the relocation of these genes might be involved in this condition.

Finally, Pim and his colleagues found that damaged DNA regions can cluster together in the cell nucleus when proteins are at work to repair those regions, forming so-called ‘repair hubs’. This even occurs if the damaged sites are located on completely different chromosomes.

From nothing to something

According to Pim, basic research can be very rewarding because of the potential for discovery and innovation, but it also comes with significant uncertainty. “Periods in which results fail to materialize can be challenging. Doing a PhD can sometimes feel like a cycle of rewarding highs and difficult lows,” Pim mentions.

The transformative moments in the projects were the highlights of Pim’s PhD. “It is so rewarding to see a long-awaited result confirm an exciting hypothesis,” Pim tells. He experienced how initially confusing or insignificant results can turn out to be a major part of a project. “To see something transform from nothing into something and to celebrate those moments with colleagues has probably been the most enjoyable experience of my PhD,” Pim concludes.