Researchers manipulate chromosomes in vivo for the first time!

Researchers manipulate chromosomes in vivo for the first time!

Researchers manipulate chromosomes in vivo for the first time!

Chromosomes, composed of DNA and protein molecules, were previously represented as dense spheres of chromatin, forming a kind of rigid, cross-linked polymer gel. Thanks to a new technique, researchers from CNRS, the Institut Curie and the Sorbonne University discovered that things were very different. By directly exerting – and for the first time – a force on the chromosomes contained in the nucleus of living cells, they observed that they are actually very fluid. A feature that allows them to move, even to reorganize freely.

Chromosomes that react to magnetic forces

Each human somatic cell has 23 pairs of chromosomes, including one pair of sex chromosomes. Each of these chromosomes carries several hundred genes. the Human Genome Project, started in 1988 and completed in 2003, allowed to map about 92% of the genome. On March 31, 2022, the Telomere to Telomere consortium announced that it had finally sequenced the remaining 8%. Geneticists now have a complete and flawless map of the approximately 3 billion nucleic bases of human DNA, a valuable tool for the diagnosis and treatment of genetic diseases.

However, the physical principles that organize the genome in the nucleus have remained unknown, notably due to the lack of tools to directly exert and measure forces on chromosomes. inhabit and to probe their material nature. However, the way genes are expressed and the stability of the genome may depend precisely on the physical organization and material properties of the genome.

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To fill this gap, Veer Keizer, a researcher at the Institut Curie, and her collaborators developed a technique to measure how a genomic locus responds to a specific force. First they attached magnetic nanoparticles to a small part of the chromosome of a living cell. Then, they applied magnetic forces of different strengths to this place, using micromagnets; it should be noted that these forces, of the order of a picoNewton, are within the range of forces that are naturally exerted in the cell nucleus (by enzymes that replicate DNA for example). The researchers were then able to measure the chromosome’s response to these stimuli for the first time.

A free polymer in a viscous environment

After a few minutes, the team observed viscoelastic shifts of several micrometers of the genomic locus in nuclear space. Their results suggest that chromosomes are fluid, even near fluid, during the interphase, that is, outside the periods of cell division. In fact, chromatin shows a higher degree of flexibility than if it behaved as a solid or gelled material during the interphase, as currently proposed.

Mechanical micromanipulation of a chromosomal locus in vivo.

Mechanical micromanipulation of a chromosomal locus in vivo. (A) Magnetic ferritin nanoparticles are injected into the cell nucleus. The micromagnets produce a local magnetic field and attract the genomic locus. (B) The force exerted on the site depends on its position with respect to the micromagnets. (C) Experiment showing the displacement of the place during the 30 minutes of traction, followed by 30 minutes of relaxation. (D) Same experiment showing each period, along with the time profile of the force. Credits: Keizer et al., Science (2022)

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Using theoretical physical models of the polymers, the team determined that chromatin behaves as a free polymer in a viscous environment (a model known as the Rouse model), with the surrounding chromatin and nucleoplasmic material not only having a weak obstructive effect. . ” Interphase chromatin was found to be liquid, with moderate topological and crowding effects, which contrasts with the common view of a crowded and intricate nuclear environment summarize the researchers in Science.

Demonstration of viscoelastic properties

The comparison of the trajectories obtained on different cells allowed to highlight and quantify the viscoelastic properties of chromatin. The initial force applied to the locus predicts some of the variability observed in the initial movement. Similarly, the recoil motion seen after the release of the force is largely predicted by the total distance the place was moved during the pull, the researchers say, confirming the elastic nature of chromatin.

Finally, the level of DNA compaction at which the force is applied will also affect the response to this force – the researchers found that denser DNA loci move faster.

>> Read also: The “microchromosomes”, probable ancestors of human chromosomes

This study provides a better understanding of how genomic elements can move under the effect of natural biological forces; it can give rise to the development of new physical models of chromosomes. ” Our new approach opens many avenues for future research, from studying the mechanics of the chromosomal interphase to disrupting genome functions, including transcription, replication, DNA damage repair and DNA segregation. “, Conclude the scientists.

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