New tool reveals hidden complexity of genome architecture

Researchers at the Berlin Institute for Medical Systems Biology at the Max Delbrück Center (MDC-BIMSB), Germany, have developed a technique called genome architecture mapping (GAM) that allows scientists to explore the genome in stunning detail. This innovative method, as detailed in a recent study published in Natural methodsreveals hidden aspects of the spatial organization of the genome that were previously invisible to scientists who relied solely on Hi-C, a tool commonly used to study Interactions with DNA.

Professor Ana Pombo, a molecular biologist and head of the Epigenetic Regulation and Chromatin Architecture Laboratory, aptly compares the difference between Hi-C and GAM. She explains, “With a black and white TV, you can see the shapes, but everything looks grey. But if you have a color TV and you look at flowers, you realize they’re red, yellow, and white, and we didn’t know that. Similarly, there is also information about how the genome is folded in three dimensions that we were unaware of.

Understanding the organization of DNA within the nucleus can provide valuable insight into the underpinnings of health and disease. Despite the daunting task of packing a 2-meter-long genome into a nucleus just 10 micrometers in diameter, cells manage to precisely organize DNA to ensure that regulatory elements come into contact with the appropriate genes at the right time, allowing the activation and suppression of genes. Any disruption of this three-dimensional configuration can lead to disease.

Dr Robert Beagrie, co-first author of the study and a molecular biologist at the University of Oxford, who previously worked in the Pombo lab, notes: “We have known for a long time that diseases are inherited. More recently, we have come to realize that much of this predisposition is due to the fact that we inherit DNA sequence variants from our parents that affect how our genes are turned on and off.

Hi-C and GAM techniques allow scientists to freeze DNA interactions and study them. Hi-C involves cutting chromatin into fragments, which are then reassembled to reveal bidirectional DNA interactions during sequencing. In contrast, GAM, initially introduced by the Pombo team in Nature in 2017, involves slicing hundreds of thin sections of individual cell nuclei and extracting DNA from each slice. The DNA is then sequenced and statistically analyzed to identify the interacting regions.

Through the use of GAM, the research team was able to construct a comprehensive map of three-dimensional interactions within the genome. By comparing this map with the existing one 3D genome maps created using Hi-C, they discovered many new interactions that had not been observed before. This discovery initially intrigued the researchers until they realized that GAM had the ability to unveil more complex interactions, with multiple regions of DNA coming together simultaneously.

Dr. Christoph Thieme, co-first author of the study and senior postdoctoral researcher at the Pombo lab, explains: “These more complex contacts contain active genes, regulatory regions and superactivators, which regulate important genes that determine the cell identity.

The researchers found that GAM captured a significantly higher number of complex interactions compared to Hi-C, which mainly detected bidirectional interactions. These two techniques are complementary, as GAM revealed invisible contacts for Hi-C and vice versa.

Beagrie expressed excitement about the study results, saying, “I was super excited to see that we had discovered a really strong effect. Clearly, these complex interactions were much more common than we previously imagined.