What chromosomes actually look like
We are used to schematic images of chromosomes from textbooks, but in real life they look different
A way to visualize a chromosome in 3D was invented by scientists from Harvard University, thereby showing how complicated its structure is.
In the image published in Cell, there is no trace of the familiar X-shape. "In 90% of cases, chromosomes do not exist like that," says medical scientist Jun–Han Su, one of the authors of the development (Su et al., Genome-Scale Imaging of the 3D Organization and Transcriptional Activity of Chromatin).
Using their new high-resolution 3D imaging method, the team began to build a chromosome map that combined 46 images of chromosomes with a wide lens and close-ups of a single chromosome. The team then recorded genomic loci along each of the DNA strands, according to the press release Picture this: Chromosomes look different than you think.
To depict something that is still too small for an image, the scientists captured connected points ("genomic loci") along each DNA strand. By connecting many dots, they were able to form an exhaustive picture of the chromatin structure.
But there was a catch. Zhuang had previously said that the number of dots they could depict and identify was limited by the number of colors they could depict together: three. Three dots cannot form a complete picture.
So, Zhuang and her team came up with a sequential approach: visualize three different loci, suppress the signal, and then visualize three more in quick succession. When using this method, each point receives two identification marks: a colored one and a round one.
Using their 3D genome maps on Google, they can begin to analyze how the structure changes over time and how these territorial movements help or harm cell division and replication.
So, the scientists connected the dots and formed an exhaustive image of the chromatin structure.
"Now we have 60 loci that are simultaneously visualized, localized and, importantly, identified," explained senior researcher Xiaowei Zhuang from Harvard University. "It is very important to define a three–dimensional organization," he said Zhuang, "to understand the molecular mechanisms underlying it, as well as to understand how this organization regulates the function of the genome."
Google 3D Genome Maps
To cover the entire genome, the team used thousands of images and turned to a language that is already used for organizing and storing large amounts of information – binary.
Essentially, the team created Google Maps 3D genome maps, which then allowed them to begin analyzing structural changes over time.
By sealing binary barcodes on different chromatin loci, scientists could display many more loci and later decipher them. For example, a molecule depicted in the first approximation receives a barcode starting with "10". With 20-bit barcodes, the team was able to distinguish 2,000 molecules in just 20 imaging cycles. "In this combinatorial way, we can increase the number of displayed and identifiable molecules much faster," Zhuang said. Using this method, the team visualized about 2,000 chromatin loci per cell, which is more than ten times more than their previous work and enough to form a high-resolution image of what the structure of chromosomes looks like in the natural environment. But they didn't stop there: they also visualized transcription activity (when RNA replicates genetic material from DNA) and nuclear structures. Using their 3D genome maps on Google, they can begin to analyze how the structure changes over time and how these territorial movements help or harm cell division and replication.
Researchers already know that chromatin is divided into different regions and domains (for example, deserts or cities). But how these landscapes look in different types of cells and how they function is still unknown. Using high-resolution images, Zhuang and his team determined that regions with a large number of genes ("gene-rich") tend to accumulate to similar regions on any chromosome. But areas with a small number of genes ("poor genes") they are combined only if they have the same chromosome. One theory is that gene-rich regions, which are active gene transcription sites, combine like a factory to allow for more efficient production.
Although more research is needed before confirming this theory, one thing is now clear: the local chromatin environment affects transcription activity. Structure affects function. The team also found that no two chromosomes look the same, even in cells that are otherwise identical. To find out what each chromosome looks like in every cell of the human body, it will take much more work than one laboratory can do alone. The team shared their data on GitHub so that other researchers could view and continue the analysis.
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