13 July

The location of a chromosome has a major impact on its fate during cell division

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The group of Geert Kops 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 were published in Nature on the 13th of July, and highlight yet another functional role of 3D genome organization in cells.

Defects 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 are 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?

In order 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 with regard to structural features of chromosomes 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 due to the fact that 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.

 

 

Geert Kops is group leader at the Hubrecht Institute, professor of Molecular Tumor Cell Biology at the University Medical Center Utrecht, Oncode Investigator and Scientific Director and head of Oncode Institute.