Force Direction Alters Gene Expression

The type and direction of the force on a cell alters gene expression by stretching different regions of DNA, researchers at the University of Illinois Urbana-Champaign, and collaborators in China found in a new study. Their findings were published in Nature Communications. 

"Force is everywhere in the human body, and both external and internal forces can influence your body far more than you may have thought," said study leader Ning Wang. "These strains profoundly influence cellular behaviors and physiological functions, which are initiated at the level of gene expression."

Wang and his collaborators developed a method that allows them to move a magnetic bead in any direction, giving them a picture of the ways forces act on a cell in 3D—they call it three-dimensional magnetic twisting cytometry. They found that the force from the magnetic bead caused a rapid increase in expression for certain genes, but the amount of the increase depended on the direction the bead moved. When the bead rolled along the long axis of the cell, the increase was the lowest, but when the force was applied perpendicularly, gene activity increased the most. When the bead was moved at a 45-degree angle or rotated in the same plane as the cell to induce shear stress, the response was intermediate.

"These observations show that gene upregulation and activation are very sensitive to the mode of the applied force when the magnitude of the force remains unchanged," Wang said. In further experiments, the researchers found that the reason for the difference lies in the method that the forces are relayed to the cell's nucleus. The cytoskeleton's main force-bearing elements are long fibers of the protein actin and when they bend due to a force, they relay that force to the nucleus and stretch the chromosomes.

"In certain diseases, such as aortic valve calcification, arterial atherosclerosis, liver fibrosis or malignant tumors, these cellular responses and adaptation go awry, causing the tissues and organs to function abnormally," Wang said. "This is the first time that the mechanism of living cells' different biological responses to the direction of forces at the level of genes has been revealed, so perhaps with our three-dimensional approach we can understand these diseases better."