Harvard Researchers Pioneer New Technology for High-Resolution, 3D Chromosome Imaging

Harvard researchers have devised a novel technology for high-resolution, 3D imaging of human chromosomes — structures that carry DNA — in single cells, in a study published in Cell in August.

Chemistry and Chemical Biology Professor Xiaowei Zhuang and her team developed a new method to analyze the effect of chromosome structure on its function. The technique involves connecting dots that represent genomic loci along each DNA chain to form a high-quality image of chromosome structure.

Zhuang’s lab imprinted binary barcodes on the loci to capture and differentiate thousands of loci per cell in fewer rounds of imaging. The lab also monitored transcription activity — the process by which DNA information is copied into RNA — and key structures in the nucleus to better understand how changes in chromatin structure affect cell division and replication over time.

Seon S. Kinrot, a graduate student researcher in Zhuang’s lab, said the project began from two separate initiatives. While another team had focused on developing RNA imaging, Zhuang and Kinrot’s team worked on optimizing these findings for DNA imaging.

“Eventually, we kind of decided to join efforts and make it into a single project that represented a platform where, depending on what type of question and what scale of structures are interested in, you could use one or both of these approaches to try to answer your question,” Kinrot said.

According to Kinrot, though there is no existing method of arbitrary-resolution, genome-wide imaging in single cells, Zhuang’s technology is promising in part because of its high detection efficiency for selected genomic loci.

“For questions that require information about specific genomic loci from single cells, I think this technology can be very, very transformative,” Kinrot said.

He emphasized that his team’s technique can observe chromatin structure in conjunction with transcriptional output.

“That's actually something that I am not aware that any other existing technology can do,” Kinrot said.

Within chromosomes, gene-dense, active regions of chromosomes (known as A chromatin) tend to interact with each other, and gene-poor regions of chromosomes (termed B chromatin) tend to interact with each other, according to Kinrot. These two types of chromatin, though, have little interaction between them.

However, Kinrot explained that the researchers met with unexpected results when studying interactions across — rather than within — chromosomes.

“We saw interactions between active chromatin, but we actually hardly saw any interaction between pairs of B chromatin loci across different chromosomes,” Kinrot said. “It was pretty similar to the degree of interaction between A and B chromatin.”

Kinrot emphasized that this kind of imaging technology, more broadly, can help researchers decipher biological systems with “a lot of contributing components,” as the interactions between those components remain largely unknown.

“I think the ability to really image all these things at the same time can be very powerful to, you know, help actually understand what these relationships are,” Kinrot said.