New technology simultaneously maps gene activity and expression

In recent years, the technology known as spatial omics has given us a deeper understanding of how cells decode and use the information in their genomes, which could shed light on the development of tissues and how to treat certain diseases. Now, researchers have further evolved this technology to get an even clearer genome-wide picture of these genetic workings. 

The results of the study, which provides critical information about how genes are switched on and off and expressed in different areas of tissues and organs, were published in Nature on March 15. The work is a collaboration between researchers from Yale University and Karolinska Institutet. 

A key part of the study is the researchers’ ability to spatially map simultaneously two crucial components of our genetic makeup, the epigenome and the transcriptome. The epigenome controls the switching mechanisms that turn genes on and off; the transcriptome is the result of those gene expressions and is what defines the cell - for instance, why a cell in the brain is different from one in the skin.  

The researchers had previously worked on spatial technologies, first to map the transcriptome, and later to map the epigenome. The epigenome can be thought of as a fuse box. You can flip the switches, but if you can’t see whether the lights are turning on, your information is limited. By spatially mapping both the epigenome and transcriptome, though, the researchers developed a technology in which both the input (switching a gene on or off) and the output (gene expression) can be detected in the same tissue section. This new technology brings unprecedented insights about gene regulation in precise locations in a tissue. 

“Now we can understand the mechanism to control gene expression, and you can also map what genes are expressed in specific locations,” said senior author Rong Fan, the Harold Hodgkinson Professor of Biomedical Engineering at Yale. “With that, we can link them together and pinpoint all possible mechanisms at a genome scale - which controls which, and whether they’re actually being controlled.” 

For this study, the researchers adapted a DNA barcoding technique they previously developed to map the epigenome. They also applied “DBiT-seq,” another technique that they developed, to map the transcriptome. The combination of these techniques allows the researchers to get extremely precise information at a minute level within an intact tissue section. 

Using both techniques to map the epigenome and transcriptome simultaneously, though, took some work. Fan credits his postdoctoral associate Di Zhang (lead author of the paper) and former postdoctoral associate Yanxiang Deng, now an assistant professor at UPenn, for “tweaking the chemistry quite a bit to make these two very distinct spatial analyses compatible.”

They applied these techniques to embryonic and juvenile mouse brains, as well as an adult human brain hippocampus.  

Being able to map both the epigenome and transcriptome in the same cell and the same tissue has been “one of the holy grails” in the field of epigenetics, which studies how genes are expressed.

“Now that we can combine the two, we can see both the mechanisms of how the genes are switched on and off, as well as the result,” said Gonçalo Castelo-Branco, professor of glial cell biology at Karolinska Institutet, Stockholm, Sweden. “This has led us to some unexpected observations, which gives us further insights into how these processes are regulated in different tissue areas and contribute to different cell fates.” 

The work could bring researchers closer to understanding potential genetic targets for drug therapy and help advance the field of personalized medicine.  

“In the future with this technology, we will be able to really understand in every single patient how those cancer-promoting genes and tumor suppressor genes are being regulated by the epigenetic mechanisms,” Fan said. “The whole epigenetic therapeutics field is just emerging, but I think our technology can potentially empower epigenetic drug discovery.”

Fan and Castelo-Branco emphasized the teamwork involved in the research. Other collaborations include the members from the group of Prof. Yuval Kluger of Yale Pathology, Prof. Kam Leong of Columbia University, Prof. John Mann and Prof. Maura Boldrini of Columbia University School of Medicine, Prof. Sai Ma of Icahn School of Medicine at Mount Sinai, Prof. Benjamin Raphael of Princeton University, and Prof. Maximillian Haeussler of University of California, Santa Cruz.