If you think of a chromosome, what comes to mind? Most people imagine the twisted ‘X’ shape seen in the media and textbooks. Chromosomes do in fact look like this for a brief period in their life cycle, but most of the time these images are inaccurate.
However, researchers from Harvard University Graduate School of Arts and Sciences are hoping to change that. In a study published in Cell, Jun-Han Su and colleagues have reported a method of creating stunning 3D images of human chromosomes that they hope will be used to educate the next generation of scientists. Capable of more than just impressive imagery, the technology could be used to understand the inner workings of our chromosomes in finer detail than ever before.
"It's quite important to determine the 3D organization," said Xiaowei Zhuang, a David B. Arnold, Jr. professor of Science, in a statement, "to understand the molecular mechanisms underlying the organization and to also understand how this organization regulates genome function."
Chromosomes are structures within our cells that contain all our DNA. The DNA is first wound around proteins to form chromatin, which is further wound and packed tightly to create chromosomes. Humans have 23 pairs of chromosomes in each cell, with one of each coming from the father and one from the mother.
Whilst we have relatively good ways of imaging chromosomes in 2D, creating an imaging technique that can visualize the tiny, densely packed chromatin in 3D is a challenge. To solve this problem, the team devised a way of deciphering the fine details of the chromosome structure – they created a genetic ‘dot-to-dot’. Within a chromosome, there are many regions of DNA in which the sequence is known to the researchers and can be tested for, called genetic loci. By imaging many loci rapidly, connecting them together and combining the deciphered structure with high-resolution microscopy images, a 3D image of the chromosome can be created in impressive detail.
The idea builds upon existing technology called fluorescence in-situ hybridization (FISH), which uses fluorescent probes to visualize specified regions of DNA, but this technology has a much higher throughput and leverages the data to impressive 3D images.
A chromosome 3D imaging technique has massive implications for understanding gene interactions within a chromosome, and the team were eager to put it to use. After the structure was created, Zhuang and colleagues analyzed the data to determine how the chromosome structure changes to most efficiently read the genes contained within. They discovered that areas with high gene content would move to similar regions of the chromosome, where it is likely high levels of gene transcription occurs, while areas of low gene content will only go to the same place if they share the same chromosome.
Despite the impressive findings, the authors outline limitations to their new method. To image the chromosome structure, specific targeted loci need to be used, so unknown stretches of DNA cannot be imaged. They also state that the imaging process may slightly alter the structure of the chromatin, which may render it less effective than alternatives when imaging extremely small structures.
The researchers will continue their work and utilize results from other labs to fully understand the structure of chromosomes in every cell of the body – an ambitious but possible goal with such technology.