The research team of Oncode Investigator Geert Kops (Hubrecht Institute) reports that the 3D location of chromosomes in the interphase cell nucleus affects how likely they are to be incorrectly transmitted to daughter cells. The results of their study highlight yet another functional role of 3D genome organization in cells.

Oncode Investigator Jacco van Rheenen (NKI) and his research team filmed stem cells in the colon and small intestine and found different levels of stem cell regulation, which has a major impact on the onset of cancer.

Both manuscripts are now published in Nature and can be read in full here and here.

Geert Kops lab: the location of a chromosome has a major impact on its fate during cell division

Normal cells have two copies of each chromosome. Most cancer cells have abnormal numbers of chromosomes due to defects occurring during cell division. Sometimes, cells contain extra copies of some chromosomes or lacking some after cell division. The Kops Group wanted to address the following question: is the chance to mis-segregate the same for all chromosomes?

To address this question, the research team provoked several conditions that promote mis-segregation of chromosomes during cell division and used single cell DNA sequencing to globally monitor the set of chromosomes in each cell.

Not all chromosomes mis-segregate equally

“Strikingly, we found that not all chromosomes mis-segregate equally”, says first author Sjoerd Klaasen, PhD candidate in the Kops lab. “We saw that some chromosomes were much more likely to be incorporated incorrectly into the daughter cells or in structures called micronuclei, than others.”

In search of what distinguishes chromosomes that are more likely to mis-segregate than others, no clear relationship regarding structural features of chromosome were found, such as centromere size or length of the chromosome arms. However, the team found a robust correlation between the 3D location of chromosomes and the chance of mis-segregation. Chromosomes that are generally more peripherally located (red in figure 1) near the nuclear membrane were more prone to be mis-segregated than chromosomes that reside in the center of the nucleus (blue in figure 1).

Figure 1. A model for position-dependant chromosome segregation defects

“When following internal and peripheral chromosomes over time, we could show that peripherally located chromosomes are more likely to be mis-segregated. This may be because they need to travel longer distances to the metaphase plate after they attach to microtubules. Moreover, peripheral chromosomes may also take longer to properly orient themselves in the metaphase plate as observed in the live cell imaging experiments”, Klaasen explains. The resulting delays may increase the likelihood of not being included in the newly forming nucleus leading to aneuploidy and micronucleus formation in the daughter cell.

Results and next steps

“It is important to realize that our results suggest that the relation between 3D position of chromosomes and mis-segregation may also contribute to tissue-specificity of genome rearrangements in different cancers” says principal investigator Geert Kops. How much of the observed tissue-specificity of genome rearrangements is due to growth selection vis-à-vis chromosome location is still an intriguing and important question to be answered.

Jacco van Rheenen lab: the importance of stem cells

Adult stem cells are the primordial mother cells of tissue, and extremely important for the maintenance and repair of the body. They are also the cells from which cancer arises. Stem cells are the only cells that live indefinitely and produce all the body's short-lived specialised cells. Up until now it was thought that stem cells can do so, because they are located in a microenvironment with signals (stem cell niche) that makes them molecularly immortal.

Different levels of stem cell regulation

By filming the stem cells in the colon and small intestine, the research team of van Rheenen found that cells must constantly move towards the center of the stem cell niche to behave as stem cells. Interestingly, significant differences have been found between the colon and small intestine by the research team. In the colon, the cells in the stem cell niche do not move to the center, which means that only cells in the center of the stem cell niche can behave as stem cells. In contrary to the small intestine, where all cells, including the cells outside the stem cell niche are able travel to the center. Meaning, that many cells can behave as a stem cell.

Impact of stem cell regulation

Their results showed that cells must constantly move towards the center of the stem cell niche to behave as stem cells.

Due to the level of regulation, a lot more cells in the small intestine compared to the cells of colon can behave like a stem cells, which has not only a major impact on the maintenance and repair of different intestinal tissues but also on chance of DNA mutations that lead to diseases such as cancer.

This research is just the first step. “Here we looked at how stem cells are regulated. And we are now particularly interested in what happens if particular cells get mutations, like mutations that can cause cancer” says van Rheenen. “The process that we revealed is important for tumour initiation, and we really want to understand how this happens and if we can change the future of these cells, in such a way so to prevent tumour initiation” he explains.