NYU Study Reveals Gravity's Subtle Effects on the Human Genome

The Human Genome Project was launched in 1990, preceded by decades of breakthroughs in genetics, and eventually produced a full sequence of the human genome. Yet the physical rules behind the genome's organization remain an active area of research, and many questions are still largely unanswered, including the impact of an omnipresent force influencing life on Earth: gravity.

A new study in the journal Science Advances addresses some of these questions using an innovative technique: creating a zero-gravity, or microgravity, environment to reveal gravity's impact on a human cell. The method serves two purposes, isolating gravity's impact on the genome by removing it as a factor in experiments, while also showing how the genome functions in outer space, where gravity is nonexistent.

"On Earth, the role of gravity is intriguing, it is a constant mechanical stress on everything," said Alexandra Zidovska, an associate professor in New York University's Department of Physics, who led the study. "We wanted to know what gravity's role is in the genome's organization and function here on Earth. To uncover it, you have to remove gravity as a force, so we simulated zero gravity in our experiments. Beyond Earth, the question of lack of gravity is also compelling: how will the human genome be affected when in outer space? We think our findings can be useful in better understanding how space travel affects us."

The human genome has a complex and compact hierarchical organization. It is a one-dimensional sequence encoded in two meters of DNA molecules packed in three dimensions inside a cell nucleus barely 10 micrometers in size, about the width of a silk fiber. Its structure is directly linked to its function, and deviations from it can lead to human diseases such as cancer and developmental afflictions. Despite their significance, the physical principles governing the genome's organization are not well understood.

"We do not know if or how the presence of gravity affects this organization and if the absence of gravity would cause genomic aberrations," Zidovska said.

To explore the question, the NYU researchers designed and built a custom laboratory device, a random positioning machine that allows for imaging of the human genome in live cells. They prepared dishes of live cells free of air bubbles, which can interfere with measurements, and the machine rotated the dishes along two independent axes in a 3D rotational path that produces simulated microgravity, similar in principle to the larger devices astronauts use in training.

The researchers also developed novel 3D rotational algorithms that simulated microgravity while minimizing the fluid flows normally generated during 3D rotation but absent in true zero-gravity conditions. They created additional algorithms to investigate the effects of those flows on the cells and the genome. Together, these advances reduced both flows and the formation of cell aggregates, which had often obscured the effects of simulated microgravity in earlier studies.

To assess the effects of simulated microgravity and flows on the cell and cell nucleus, the researchers compared cells exposed to simulated microgravity with minimized flows, cells exposed to strong flows, and cells with no exposure at all. After exposing cells to either condition for 24 hours, the team used sophisticated imaging techniques to capture the cells and conduct a detailed physical analysis, including changes in cell shape and volume, nuclear shape and volume, the nuclear envelope, the genome, and the nucleolus, the largest liquid condensate in the nucleus.

The results showed that cell shape became elongated when exposed to flows but remained unchanged under simulated microgravity, while the volume of the cell nucleus increased after exposure to zero gravity, indicating gravity normally diminishes it. Despite these changes to the nucleus's shape and volume, the thickness and structure of the nuclear envelope remained unchanged, suggesting gravity has minimal impact on those traits. The genome inside the cell nucleus maintained its physiological organization and motions after 24-hour exposure, and simulated microgravity did not cause DNA damage, though DNA damage did occur when cells were exposed to flows. The nucleolus became smoother after exposure to either simulated microgravity or flows. Overall, a day-long exposure to simulated microgravity led to rather subtle changes, which the researchers say could amplify over longer periods and affect cell physiology.

"Our data show that the genome, its organization, and dynamics are incredibly robust and seem unaffected by gravity, or lack thereof, after 24 hours," Zidovska said. "In the same way, these results suggest that the physical organization of the human genome may undergo minimal changes in outer space during comparable times. However, such changes could occur during longer exposures and due to DNA damage occurring in space."

The paper's other authors included Nikitas Kanellakopoulos, an NYU doctoral student; NYU undergraduate students Manav Patel, Brandon Sato, and Melaina Lawrence; and Leif Ristroph, an associate professor at NYU's Courant Institute School of Mathematics, Computing, and Data Science. The research was supported in part by grants from the National Science Foundation and the National Institutes of Health.

CONTACT: https://doi.org/10.1126/sciadv.aeh3116