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Imaging chromatin architecture at the genome scale

Fluorescence method visualizes spatial arrangement of more than 1,000 DNA loci across the genome

by Celia Henry Arnaud
August 26, 2020 | A version of this story appeared in Volume 98, Issue 33


Map of more than 1,000 genomic loci in human chromatin color-coded by the chromosomes to which they belong.
Credit: Cell
This map of human chromatin was obtained by fluorescence imaging of more than 1,000 genomic loci. Each locus (spheres) is color-coded according to the chromosome to which it belongs.

The three-dimensional conformation of the DNA-packaging material chromatin influences gene regulation, but so far biologists have only been able to visualize it indirectly. Sequencing-based methods show what parts of the genome are close to one another, but such methods can’t directly reveal the spatial location of individual genes or markers, called loci, within the cell nucleus.

Now, Xiaowei Zhuang, Bogdan Bintu, and coworkers at Harvard University and the Howard Hughes Medical Institute have developed a fluorescence imaging method that allows them to visualize the positions of more than 1,000 loci across the human genome (Cell 2020, DOI: 10.1016/j.cell.2020.07.032). The method could allow biologists to answer questions such as how genome organization affects gene-expression patterns in different types of cells.

The researchers use fluorescence microscopy to image the location of sequence-specific probes. Previously, they used sequential rounds of labeling and imaging to identify tens of genomic loci, a few loci per round. But such an approach is challenging and time consuming to do on the genomic scale.

To image many more loci at a time, the researchers took a combinatorial approach, imprinting unique bar code probes onto targeted genomic loci. They then read them out with fluorescently labeled probes that can detect the bar codes. The researchers determine the identity of each locus from the combination of rounds and color channels in which it appears. This approach allows them target many more loci simultaneously. They adapted the approach from a method that they previously used for imaging RNA.

“This approach scales much faster than the sequential imaging method,” Zhuang says. “We can image many more genomic loci and identify and localize them in fewer rounds of imaging.”

In addition to imaging genomic loci, the researchers also imaged the beginning stages of RNA production and other nuclear structures. “We placed the chromatin organization at the genomic scale in its native structural and functional context,” Zhuang says.

“They’ve shown that you can now interrogate thousands of sites that are uniformly distributed across the length of the genome. And that’s remarkable,” says Erez Lieberman Aiden of Baylor College of Medicine and Rice University, who is a pioneer in the sequencing-based methods of determining genomic architecture.

Bintu says there’s a lot left for biologists to work on. The team has made both the methods and the data freely available. Bintu explains that for this initial study, the group imaged regions that would uniformly span the genome. Biologists interested in particular regions could design their own probes and follow the imaging protocol established by the team.

Such studies are already underway. “Sometimes the most compelling demonstration of the power of a method is not how beautiful the images are but the major discoveries you make with it,” Zhuang says.



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