Method to probe chromosomes shows how DNA can bend

Light used to bind distant sections of DNA together, shows that chromosomes behave like an elastic material and also like a fluid.

DNA strands, shaped in a double-helix structure, are very long, with an adult human's total DNA stretching around two metres. To fit these lengths of DNA within each cell's nucleus, DNA is tightly coiled around proteins called histones to form chromatin, which is then further wrapped to form chromosomes. A group from Princeton University, New Jersey, attached two droplets (biomolecular condensates, a type of non-membrane bound organelle) containing programmable proteins to different sections of specific loci on chromosomes in order to physically manipulate the DNA in a controlled way.

'What's happening here is truly incredible. Basically, we've turned droplets into little fingers that pluck on the genomic strings within living cells,' said Dr Cliff Brangwynne, senior author of the study and director of Princeton's Omenn-Darling Bioengineering Institute.

These droplets were irradiated with blue laser light, causing both droplets to grow and combine together. The laser light was then turned off, and the droplets shrank, allowing the two sections of different strands of DNA to join.

The expression of a particular gene, formed of sections of DNA, depends on how compact it is wound around the histones, with those more strongly coiled being more difficult to unravel and express. Thus, by repositioning particular genes within chromosomes without changing the sequence of DNA, the study set to determine whether the expression of certain genes can be monitored when moved to different positions within the chromosome.

This technique differs from CRISPR, which cut sections of DNA and re-sequences it. This new method, does not edit the genome, but instead reshapes the DNA. Previously, repositioning sections of DNA could take hours or even days, relying on its random movements, however this new process requires only ten minutes.

'We haven't been able to have this precise control over nuclear organisation on such quick timescales before,' said Dr Brangwynne.

This paper, published in the journal Cell, sought to measure the force required to move sections of DNA, whether these sections returned to their original positions, and by how much force. Previous studies have concluded that chromatin likely acts like a liquid, while others believed it behaves more like an elastic solid. The researchers have now identified that chromatin within the chromosomes behaves both like an elastic and like a liquid, they then used this knowledge to manipulate the DNA physically, bending strands back in order to probe the genome.

By understanding the mechanisms and effects of gene expression, the cause and progression of numerous diseases can potentially be uncovered.

'We can use this technology to build a map of what's going on in there and better understand when things are disorganised like in cancer. If we can control the amount of expression by repositioning the gene, there is a potential future for something like our tool,' said Dr Amy Strom, first author of the study and postdoctoral researcher in the Brangwynne group at Princeton.