Videos showing for the first time how small circles of DNA adopt dance-like movements inside a cell have been developed by researchers in Yorkshire.
The footage, created by a team of scientists from the Universities of Leeds, Sheffield and York, and recorded at UCL, is based on the highest resolution images of a single molecule of DNA ever captured.
They show in unprecedented detail how the stresses and strains that are placed on DNA when it is crammed inside cells can change its shape.
Previously scientists were only able to see DNA by using microscopes limited to taking static images. But now the Yorkshire team has combined advanced atomic force microscopy with supercomputer simulations to create videos of twisted molecules of DNA.
The images are so detailed it is possible to see the iconic double helical structure of DNA, but when combined with the simulations, the researchers were able to see the position of every single atom in the DNA and how it twists and writhes.
Credit: University of Sheffield
Dr Alice Pyne, Lecturer in Polymers & Soft Matter at the University of Sheffield, who captured the footage, said: "Seeing is believing, but with something as small as DNA, seeing the helical structure of the entire DNA molecule was extremely challenging.
"The videos we have developed enable us to observe DNA twisting in a level of detail that has never been seen before."
The study, Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides, is published in Nature Communications.
Every human cell contains two metres of DNA. In order for this DNA to fit inside our cells, it has evolved to twist, turn and coil a process called supercoiling. That means that loopy DNA is everywhere in the genome, forming twisted structures which show more dynamic behaviour than their relaxed counterparts.
To investigate how this process works, the research team studied small "packets" of genetic information called DNA minicircles, engineered and isolated from bacteria. DNA minicircles are special because the molecule is joined at both ends to form a loop. This loop enabled the researchers to give the DNA minicircles an extra added twist, making the DNA "dance" more vigorously.
When the researchers imaged relaxed DNA, without any twists, they saw that it did very little. But when they gave the DNA an added twist, it suddenly became far more dynamic and could be seen to adopt some very exotic shapes.
These exotic "dance moves" were found to be the key to finding binding partners for the DNA.
How the findings aid future research
Gene therapy is the use of nucleic acids such as DNA to repair, replace, or regulate genes to prevent or treat human disease. In the past few decades, hundreds of gene therapy candidate genes have been uncovered, yet very few of these have turned into target therapies because of the challenge of delivering the gene therapy.
Professor Lynn Zechiedrich from Baylor College of Medicine in Houston Texas, who made the minicircles used in this study, has found a way to design supercoiled minicircles or, minivectors for use in gene therapy by inserting short genetic messages.
Professor Zechiedrich said: "The research team in Yorkshire have developed a technique that reveals in remarkable detail how wrinkled, bubbled, kinked, denatured, and strangely shaped they are!
"We have to understand how supercoiling, which is so important for DNA activities in cells, affects DNA in hope that we can learn how to mimic or control it someday."
Dr Massa Shoura from Stanford University, who has detected DNA minicircles in human cells, said: "Very little is currently understood about the function of circular DNAs in cells, but there is a chance they could be used as markers for early detection of disease."
Dr Sarah Harris, Associate Professor in the School of Physics and Astronomy at the University of Leeds, who supervised the research, said: "The laws of physics apply just as well to the molecules that make up living systems as to sub-atomic particles and galaxies. The synergy between our experiments and computer models shows we are beginning to understand the physics underlying supercoiled DNA. This insight should help researchers such as Professor Zechiedrich design bespoke minicircles for future therapies."
Top image: A visualisation of a DNA minicircle
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