Credit: Julia Fekecs, National Human Genome Research Institute

Researchers at the Berlin Institute of Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB) have developed a technique called Genome Architecture Mapping (GAM) allowing the identification of previously invisible genomic connections.

Ever since the revelation of its basic structure seventy years ago, scientists have been trying to understand the organization of DNA as well as its implications in health and disease. A popular tool to investigate genomic interactions is known as Hi-C—allowing researchers to detect chromatin interactions in the nucleus by using a chemical to stick close regions of the DNA together.

However, this technique may be insufficient in detecting all possible genomic interactions present in the cell. Reporting in Nature Methods, scientists have now developed a new tool known as Genome Architecture Mapping (GAM) based on taking hundreds of thin slices of cell nuclei from individual cells, extracting the DNA present and finally sequencing it in order to understand which regions interact.

“With a black-and-white TV, you can see the shapes but everything looks grey. But if you have a color TV and look at flowers, you realize that they are red,  yellow and white and we were unaware of it. Similarly, there’s also information in the way the genome is folded in three-dimensions that we have not been aware of,” explained Ana Pombo, PhD, molecular biologist at the MDC-BIMSB and co-author of the study in a press statement.

Using the GAM technique, the team were able to create a map of three-dimensional genomic interactions and compare it with existing 3D maps of the genome that had been created using the Hi-C method. Upon comparison, the scientists found many new interactions in the GAM—created map that they were able to explain by realizing that in these cases the interactions were more complex, with multiple DNA regions coming together at the same time.

According to the scientists, these more complex interactions could be responsible for active genes, regulatory regions and super enhancers which control important genes determining the identity of cells and therefore their role in health and disease.

“We’ve known for a long time that diseases run in families,” said Robert Beagrie, PhD, co-first author of the study and a molecular biologist at the University of Oxford, formerly at the Pombo lab. “More recently, we’ve come to understand that a great deal of this predisposition is because we inherit DNA sequence variants from our parents that affect how our genes are switched on and off.”

Despite unveiling genomic interactions invisible using the Hi-C method, the GAM technique missed out on some of the information available using Hi-C, proving the two methods to be complementary rather than one being better than the other.

“I was super excited to see that we had uncovered a really strong effect. It is clear that these complex interactions were much more common than we had previously appreciated,” Beagrie concluded in a press statement.

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