Newswise — Prior to the 1980s, individuals with black-and-white television sets were unaware of what they were missing until they upgraded to a color TV. A similar paradigm shift could take place in the field of genomics, as researchers at the Berlin Institute of Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB) have introduced a groundbreaking technique called Genome Architecture Mapping (GAM). This innovative approach enables scientists to explore the genome in vivid technicolor, revealing hidden spatial structures that were previously concealed from those relying solely on Hi-C, a widely-used DNA interaction analysis tool developed in 2009. A recent study conducted by the Pombo lab and published in Nature Methods highlights the profound insights uncovered by GAM.
Professor Ana Pombo, a molecular biologist and leader of the Epigenetic Regulation and Chromatin Architecture lab, explains the analogy further, stating, "Using a black-and-white TV, you can discern shapes, but everything appears in shades of gray. However, when you upgrade to a color TV and observe flowers, you become aware of their vibrant red, yellow, and white hues that were previously unnoticed. Similarly, the three-dimensional folding patterns of the genome hold valuable information that has remained largely unknown to us."
The comprehension of DNA organization holds the key to unraveling the foundations of both health and disease. Despite our cells containing a 2-meter-long genome, they intricately pack it within a nucleus of approximately 10 micrometers in diameter. This packaging is precisely orchestrated to ensure that regulatory DNA elements make contact with the appropriate genes at specific moments, effectively controlling their activation and deactivation. However, any alterations to the three-dimensional configuration can disrupt this intricate process, leading to the onset of various diseases. By studying and understanding these structural changes, we can gain valuable insights into the mechanisms underlying disease development.
Dr. Robert Beagrie, co-first author of the study and a molecular biologist previously affiliated with the Pombo lab at the University of Oxford, highlights the long-standing recognition that diseases often exhibit familial patterns. He further explains, "In recent years, we have gained a deeper understanding that a significant portion of this predisposition arises from inheriting DNA sequence variants from our parents. These variants directly influence the regulation of our genes, determining when they are activated or deactivated." This emphasizes the crucial role that genetic inheritance plays in shaping our susceptibility to various diseases by impacting gene expression patterns.
GAM provides more complex information
Advanced methodologies like Hi-C and GAM empower scientists to investigate and examine the interactions occurring between regulatory sequences and genes. In Hi-C, the chromatin is enzymatically fragmented into smaller fragments, which are then reconnected in a manner that unveils the two-way DNA interactions when subjected to sequencing. On the other hand, GAM, initially introduced by the Pombo team and published in "Nature" in 2017, involves the extraction of DNA from hundreds of thin slices of individual cell nuclei. Subsequently, the extracted DNA is sequenced, and through statistical analysis of the data, researchers gain insights into the regions that engage in interactions. These techniques provide researchers with a means to effectively freeze and study the intricate molecular interactions happening within the genome, shedding light on the regulatory dynamics of gene expression.
Utilizing the GAM technique, the research team successfully constructed a comprehensive map illustrating the three-dimensional interactions within the genome. Upon comparing this map with previously generated 3D genome maps using Hi-C, the team made a remarkable discovery: the GAM map revealed numerous novel interactions that had not been observed before. Initially puzzled by this discrepancy, they eventually realized that GAM captured more intricate and complex interactions. These interactions involved multiple regions of DNA converging simultaneously. Dr. Christoph Thieme, co-first author of the study and a senior postdoctoral fellow in the Pombo lab, explains the significance, stating, "These complex contacts encompass active genes, regulatory regions, and super enhancers, which are crucial in governing important genes responsible for determining the identity and characteristics of cells." The enhanced resolution and detailed insights provided by GAM offer a deeper understanding of the dynamic interplay between genomic elements and their role in gene regulation.
Utilizing the GAM technique, the research team successfully constructed a comprehensive map illustrating the three-dimensional interactions within the genome. Upon comparing this map with previously generated 3D genome maps using Hi-C, the team made a remarkable discovery: the GAM map revealed numerous novel interactions that had not been observed before. Initially puzzled by this discrepancy, they eventually realized that GAM captured more intricate and complex interactions. These interactions involved multiple regions of DNA converging simultaneously. Dr. Christoph Thieme, co-first author of the study and a senior postdoctoral fellow in the Pombo lab, explains the significance, stating, "These complex contacts encompass active genes, regulatory regions, and super enhancers, which are crucial in governing important genes responsible for determining the identity and characteristics of cells." The enhanced resolution and detailed insights provided by GAM offer a deeper understanding of the dynamic interplay between genomic elements and their role in gene regulation.
In contrast, Hi-C predominantly captured two-way interactions, while GAM detected a significant portion of contacts that were not observable using Hi-C, and vice versa. These two techniques are mutually beneficial, as they complement each other by revealing different sets of interactions.
"I was incredibly thrilled to discover that we had unveiled a highly robust effect," Beagrie expresses with enthusiasm. "It is evident that these intricate interactions were far more prevalent than we had previously realized."
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