In addition, new research from Duke University has revealed some fascinating new information about these less-familiar regions of the genome. Though only around 1% to 2% of the genome encodes for genes, the other 98% plays an important role in establishing cell identity and dictating how cells react to their surroundings. This groundbreaking study, led by postdoctoral fellow Brian Cosgrove, highlights the significance of these “dark” regions of the genome in influencing susceptibility to various diseases.
The study underscores the idea that the vast majority of the genome, once considered non-coding or inactive, is essential for understanding how cells react to their surroundings. This research team has been collaborating intimately for the past 10 years to unpack these layers. This interdisciplinary team features Charlie Gersbach, the John W. Strohbehm Distinguished Professor of Biomedical Engineering and Director of the Duke Center for Advanced Genomic Technologies (CAGT).
In these examples, Cosgrove and Gersbach engineered hydrogels that replicate a range of tissue stiffness. Beyond developing unique mechanical environments, they plan to study how these mechanics affect cell behavior. Cells were then cultured on these gels and monitored to track their responses over time. Yarui Diao, an associate professor of cell biology and member of the Duke CAGT, played a key role. She showed that the mechanical conditions used have a dramatic impact on how mechanoenhancers interact with their gene targets.
“Only 1%–2% of our genome encodes for genes. The other 98% of the genome clearly plays an important role in shaping cell identity, response to the environment, and susceptibility to disease, but until recently we didn’t have the tools to probe the function of this dark part of our genome,” said Crawford.
This culturally immersive approach was so successful for our public outreach. In only 20 hours, it showed us marked changes in baselines of gene expression levels and changes across almost fifty thousand genomic areas. The resulting data indicates a deep connection between the mechanical environment of a cell and its biological behavior.
“In just 20 hours on the different gels, we observed changes in the levels of thousands of genes and the structure of almost fifty thousand regions of the genome,” noted Hoffman from the research team.
This lab’s work emphasizes the importance of mechanical stimuli coming from a cell’s microenvironment. By regulating physiological processes, these stimuli actively regulate essential processes such as growth, differentiation, and migration. The stakes are high too, especially in areas such as fibrotic disease and cancer. Alterations in tissue architecture are key to understanding and targeting these diseases.
“This underscores the profound effect of the mechanical microenvironment on cell biology and clarifies how changes in tissue structure can play a significant role in diseases like fibrosis and cancer,” added Hoffman.
Gersbach remarked on the collaborative nature of this research effort, stating, “The project is a great example of highly effective and unique collaboration across engineering, science, and medicine at Duke with many contributors throughout Duke CAGT.”
“This highlights the type of products that our center is designed to produce by marrying technology with biomedical science, as well as engineering approaches with patient-derived samples,” he concluded.
Whatever the future holds, Cosgrove was clear on one point — mapping these mechanoenhancers would be a serious boon. He stated, “Mapping these mechanoenhancers can improve our mechanistic understanding of diseases that involve changes to tissue mechanical properties, like fibrosis and cancer, and possibly lead to new drug targets or methods for engineering how cells sense pathologic mechanical environments.”