Study Reveals New Way Cells Organize Their Genomes

Every cell in the body constantly monitors changes in its environment, from exercise to aging to disease and medical treatments. Cells respond to change by rapidly adjusting how they transcribe their DNA.

A study led by Northwestern Engineering’s Vadim Backman suggests that the physical and chemical environment inside the nucleus also plays an active role in how cells regulate their genomes.

This is especially relevant in cancer, where some cells respond to treatment while others adapt and survive by developing chemoresistance. Backman and his team found that changing the physical organization of chromatin—DNA packaged with histone proteins inside the cell nucleus—altered how cancer cells responded to chemotherapy. This suggests that the organization and folding of DNA inside the cell nucleus itself can influence treatment outcomes and that DNA organization is an active part of how cells respond to their environment.

“Understanding and controlling that organization could lead to new approaches for making cancer therapies more effective and, in the future, for treating other diseases in which genome organization becomes disrupted,” Backman said. 

Backman is the Sachs Family Professor of Biomedical Engineering and Medicine and director of the Center for Physical Genomics and Engineering. This work was presented in the paper “Chromatin Packing Domain Engineering Through the Manipulation of Nuclear Cationic States,” published Aug. 13 in Advanced Science.

For decades, researchers have focused on the molecular machinery that regulates the genome, including transcription factors, chromatin remodeling complexes, histone modifications, and architectural proteins. While these mechanisms remain fundamental to genome regulation, the Backman team’s work expands this framework by showing that the nucleus’s physicochemical environment also plays an active role in organizing the genome.

Nearly every cell in the body contains the same roughly two meters of DNA, yet cells use that genetic blueprint to perform vastly different functions. One reason is that DNA is folded into a complex three-dimensional structure inside the nucleus, and the study found that magnesium helps regulate this organization. Specifically, the researchers found that nuclear magnesium regulates chromatin packing domains, the structural units that help organize DNA inside the nucleus.

 “Together, our findings demonstrate that the genome is regulated not only by its DNA sequence and molecular machinery, but also by its physical organization. More importantly, we reveal that this organization can be rapidly and reversibly controlled through changes in the nucleus's ionic environment,” PhD student Paola Carrillo Gonzalez said. “This provides a new framework for understanding how cells regulate genome function and suggests that manipulating chromatin architecture could become a new strategy for influencing cell behavior and therapeutic responses.”

This study is part of a broader effort to understand the genome not only as genetic information, but also as a physical structure that cells actively organize and regulate. Scientists have long known that DNA must be tightly folded to fit inside the nucleus, and more recent research has shown that it is organized into nanoscale structures that help control how cells use their genes.

The Backman group’s recent findings transform these structures from features that scientists can observe into structures they can experimentally manipulate, providing a way to directly test how the physical organization of the genome affects cells.

“Ultimately, our goal is to move from understanding chromatin packing domains to intentionally controlling them. If we can learn how cells regulate the physical organization of their genome, we may one day soon be able to engineer chromatin packing states to influence cell function,” postdoctoral fellow Cody Dunton said. “This could lead to new strategies for improving responses to cancer therapies, promoting tissue regeneration, or treating diseases in which genome organization becomes disrupted.”

Backman and his research team showed that these structures can be rapidly and reversibly remodeled by changing the chemical environment inside the nucleus, but they still do not fully understand how the structures are created and maintained.

Magnesium appears to play an important role, but many questions remain about how cells regulate the chemical environment in different parts of the nucleus and how those changes affect genome organization during change such as development, aging, and stress. Answering those questions could reveal precisely how cells reshape their genomes to adapt to changing conditions, and lead to new techniques for controlling that adaptation.