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New research uses magnetic nanoparticles to manipulate genomic loci

Written by Miyako Rogers, Science Writer

Research published in Science describes an innovative new technique to manipulate specific genomic loci using magnetic nanoparticles. This allowed the researchers to probe the physical properties of an interphase chromosome by measuring its response to a magnetic force. Results from this study reveal that chromatin behaves like a fluid, challenging previous research that suggested chromatin is a stiff gel with solid-like properties. These findings could significantly impact our understanding of how DNA-based biological processes, such as DNA damage and repair, function.

Manipulating genomic loci

Previous attempts to investigate the material properties of chromatin have been limited by a lack of tools to directly measure and exert forces on chromatin in vivo. Up until now, studies have only been able to manipulate large structures. This makes it challenging to distinguish mechanical responses between the nucleus and chromatin itself, leading to contradictory results. To tackle this problem, researchers developed a new method of targeted micromanipulation of specific genomic loci in the nucleus of a living cell.

Cells were first genetically engineered to contain an artificial genomic array inserted at a specific genomic locus. Magnetic nanoparticles (MNPs) were then targeted to the array using a constitutively expressed fusion protein, which acted as a tether. Once the MNPs were injected into the cell’s nucleus, they accumulated at the array and could be manipulated using controlled magnetic forces.

Figure 1 ¦ Illustration showing MNPs (ferritin-GFP) injected into cell nucleus, as well as fusion protein (anti-GFP-nanobody, mCherry, TetR complex) and artificial genomic array (tetO array). Also shows the magnetic pillar which exerts magnetic force on the tethered MNPs. (Source: Science)

Chromatin has fluid-like properties

Researchers found that very small, near pico-newton forces could easily move a genomic locus across the nucleus in just a few minutes. This indicates that interphase chromatin has fluid-like properties, contradicting previous studies that described chromatin as a stiff gel.

This could be for several reasons: Previous studies used micrometre-sized beads, whilst in this study, the locus used is very small and so may be able to pass through surrounding chromatin more easily. This could be because chromatin is a weak gel that allows for fluid motions at a smaller scale but is stiff at larger scales. Another explanation is that chromatin could contain small pockets of stiff gel embedded within the fluid structure. This would also explain why the travelling locus encountered obstacles as it moved across the nucleus.

Implications for the future

These new results describing the physical properties of chromatin have big implications for our understanding of many different biological processes. For example, the trafficking of genes upon transcriptional activation requires nuclear reorganisation and the fluid-like nature of chromatin could be what allows for this. Furthermore, these results may also explain how molecular motors such as SMC complexes and RNA Pol II can reorganise the genome, as the magnitude of forces and the time-scale of force exertion are similar to how these proteins work.

And that’s just from the results of this study. This new method of manipulating genomic loci opens many avenues for future research. Manipulating different genomic loci in different cell types will help us understand if these findings are consistent in various biological contexts. Moreover, this technique will allow other researchers to investigate processes like transcription replication, DNA damage, DNA repair and chromosome segregation, allowing us to develop new theories of how the genome can be reorganised.