The human genome is like a big ball of yarn, made up of 3 billion molecular units arranged in sequence and then wrapped up around itself. Within this ball of yarn are your genes, which are regions of DNA that get copied and then turned into miniature molecular machines called proteins. The three-dimensional structure of the yarn dictates which of your genes get turned into proteins, and when this system fails, disease develops. But until now, it has not been possible to visualize how different regions of DNA talk to each other across space and time.
A team at Stanford led by Stanley Qi, associate professor of bioengineering in the Schools of Engineering and Medicine and Institute Scholar at Sarafan ChEM-H, and W.E. Moerner, Harry S. Mosher professor of chemistry in the School of Humanities and Sciences, combined their expertise in DNA technology and super-resolution imaging to develop a new tool that can light up any region of the genome in any living cell and enable scientists to watch how different regions interact with one another. The tool, reported in Cell on April 15, could help scientists understand how certain genes get turned on and off in healthy cells and in diseases like cancer.
Previously, researchers were only able to see snapshots of DNA interactions at different timepoints in preserved cells. Much like the difference between a photograph and a video, their technology reveals a fourth dimension - time - in cells that are alive and dynamically changing.
"Our work turns Instagram into YouTube," said Qi. "It gives a direct understanding of what's going on over time in cells."
Of particular interest are regions of DNA that do not contain genes. Only about 2% of the 3 billion units in our DNA ever get converted into proteins, a process known as gene expression. Scientists used to refer to the other 98% as junk DNA, since it did not seem to have a clear purpose. We now know that these mysterious DNA regions contain important features that control gene expression.
"They are like the software controlling the DNA program," said Qi.
These detailed movies of previously overlooked pieces of genome could offer new fundamental insights into biology. In addition, seeing how the "software" changes in real time in healthy cells compared to diseased ones could provide clues about faulty gene expression related to illness.
Fluorescent mailmen
The first step in making this tool was figuring out how to observe a specific region of the genome within the abundant complexity of the DNA yarn ball. For this, the researchers turned to a version of the gene editing technology called CRISPR. This version of CRISPR uses an engineered protein called dCas9, together with an RNA molecule that acts as a mailing address for a particular site in the genome. This enables the dCas9-RNA complex to act like a mailman, finding and attaching itself to one desired DNA address - all while carrying a fluorescent dye molecule that is visible as light under the microscope.
The researchers made their fluorescent signal brighter by sending a flock of molecular mailmen to span unique DNA addresses within the same genetic zip code, lighting up the DNA "street" of any gene they wanted to study. Under a traditional light microscope, this activity would look like a blurry blob because the movements of DNA are on the order of tens of nanometers - 5,000 times smaller than the width of a human hair and well below what a traditional light microscope can resolve. To overcome this limitation, the Qi lab turned to the expertise of Moerner and his team, who helped pioneer techniques to detect light emitted from single fluorescent molecules, a feat that earned Moerner the Nobel Prize in Chemistry in 2014.
Super-resolution microscopy techniques to detect light from single molecules are now widely used, but a limitation of many microscopes is the inability to collect information about how a molecule moves in all three dimensions at the same time. Scientists can watch a piece of DNA jiggle left and right, but the up and down motion would only be captured in snapshots that miss big chunks of time. To fill in the gaps, Moerner and team use an optical trick in their microscope to extract simultaneous position information about DNA in all three dimensions at once. Much like a prism can split visible light into its components to produce a rainbow, passing light through other materials causes it to shapeshift in different ways.
"There are actually a lot of amazing things that can be done with light. What we did was add a special optical component that re-scrambles one spot of light into two spots, so that depth information is encoded in the angle between the two spots," Moerner explained.
Of course, those spots are the fluorescent mailmen that the team appended to DNA. And the angle is the critical missing piece of spatial information that allowed the researchers to capture the full picture of DNA architecture in real time.
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Watching the 3D nanoscale interactions between two sites on DNA - the enhancer and promoter regions of a gene called FOS - during gene expression. | Ashwin Balaji
