Position and separation error frequency of nuclear chromosomes

Article | November

Aneuploidy refers to the state where the number of cell genome content deviates from the number of polymers. The occurrence of abortion and development syndrome in human body will be closely related to the occurrence of tumors [1]. Non -rectifier is usually caused by chromosomal separation errors during cell division, such as changes in microtubuctance dynamics, super stabilizing silk microtuba connection, internal agglomeration problems, or spindle assembly checkpoints (SAC ) Activation weakened and so on. [2]. The errors of wire division also caused the nuclear membrane to rupture due to the formation of micro -nucleus, and a wide range of genomes caused a non -rectification body. Different non -rectification modes were shown in cancer. So is the appearance of different modes of non -rectification? If not, what is the deviation factors that cause non -complete bodies?

2022年7月13日，荷兰乌得勒支大学医学中心Geert J. P. L. Kops研究组在Nature上发表了文章Nuclear chromosome locations dictate segregation error frequencies，利用有丝分裂后单细胞DNA测序scKaryo-seq（Single-cell karyotype sequencing ) Technology, discovers different chromosomes with different separation errors, and then explore the influencing factors of the deficiency of the non -rectifier structure, which provides new thinking for understanding the process of cancer genomic evolution and the mechanism of non -rectification.

In order to establish the frequency and characteristics of the separation of a single chromosomal error, the author uses the single-cell nuclear sequencing technology SCKaryo-Seq [3]. This technology can be used to determine the copy number of all chromosomes in the single cells in high -fidelity and high -throughput. The authors use a chromosomal that is a small molecular molecular inhibitor that is a CPD-5 mini-splitase MPS1 small molecular molecular inhibitor. Under low concentration, chromosomes that can cause misplace and lagging separation in most cells. This is very similar to that of wire division errors often appear in cancer cells. The author subsequently performed the SCKaryo-seq of hundreds of chromosomal separation errors in CPD-5 for 4 hours. It was found that each non-rectification of 5.5 chromosome separation errors were found. With structural chromosomes, a non -rectifier landscape analysis map can be established.

Through the SCKaryo-SEQ chart established, the author found that the probability of error division in chromosomes 1-5, 8, 11 and X chromosome is significantly increased significantly than the expected random errors, and chromosomal 15 and 19-22 are compared The expected random probability is much lower. By using twice fibroblasts and human intestinal organ cell lines, the authors have also found similar chromosomal separation errors. Further, the authors further verified that the non-rectifier landscape characteristics observed by SCKaryo-Seq observed by SCKaryo-seq were caused by chromosomal split deviating deviations. In addition, in other ways, such as separation errors caused by Aurora B small molecule inhibitors, chromosomal derivatives caused by low concentration of Nokdazazo, etc., the initial deviation of specific chromosomal separation errors will occur.

Error split chromosomes are usually wrapped in micro -nucleus. The chromosome in the micro -nucleus will lead to a wide range of dyeing weight. This is an important factor that promotes the development of tumor genome. Therefore, the authors want to know Whether the content of micro -nucleus also has similar initial deviations. To this end, the authors separate the micro-nucleus through fluorescence activation cell sorting and evaluate their content through sequencing. The author refers to the technology as MN-SEQ. The authors found that the content of micro -nucleus was correlated with the chromosomes separated by error, and they all appeared non -random. Therefore, chromosomal with a high probability of separation errors will be trapped in microcontrol nucleus, and chromosomal separation errors in cancer cells are not random.

So what is the original source of this chromosome separation error? The author proposes a hypothesis that peripheral chromosomes are easier to separate more errors than centers, because they need to take a farther distance to reach the equatorial board. Therefore, the distance between the distance of the core may be the reason why the chromosomal split error occurs in the initial deviation. To this end, the author confirms the experiments such as the real -time tracking of the chromosome position, the real -time tracking of CAS9 protein, and the re -positioning of the chromosome. The chromosomes with a larger distance from the central position are more prone to the tendency to separate errors. In addition, large chromosomes are more likely to occur in non -rectification of chromosomes, because these chromosomes are also preferred in the outer peripheral area.

Generally speaking, the author's work through double body cell lines and organ cells, etc., through the introduction of mitotic chromosomal separation errors and single -cell sequencing, found that the frequency of chromosomal errors is not random, and the chromosomes that are separated by error separation are also separated. Will be prioritized into the micro -core. In addition, the author found that the initial deviation of this chromosome separation error was related to the position of the chromosome in the nucleus. The results of the study reveal the direct connection between the position of nuclear chromosomes, the frequency of separation errors, and the microcirculation content, which is of great significance for understanding the origin of a specific non -rectifier in the process of compliance with tumor genome and development. Original link:

https://doi.org/10.1038/s41586-022-04938-0

references

1. Van Jaarsveld, R. H. & KOPS, G. J. P. L. Differentce Makers: Chromosomal Instability Versus Aneuploidy in Cancer. Trends Cancer 2, 561–571 (2016).

2. Compton, D. A. Mechanisms of Anuploidy. Curr. Cell Biol. 23, 109–113 (2011)

3. Bolhaqueiro, A. C. F. Et Al. Ongoing Chromosomal Instability and Karyotype Evolution in Human Colorectal Organoids. NAT. 51, 824–834 (2019)

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