A group of researchers has unveiled unexpected links between gene activity, how compactly the genome is organized, and the overall movements within the genome. These insights shed light on the genome’s structure, which significantly influences gene regulation and expression. The results enhance our comprehension of the mechanics involved in the movements of individual genes during transcription – dysfunctions of which could lead to neurological and cardiovascular ailments, as well as cancer.
A group of researchers has unveiled unexpected links between gene activity, how compactly the genome is organized, and the overall movements within the genome.
These discoveries, detailed in the journal Nature Communications, improve our knowledge of how the motions driven by transcription occur in individual genes. Such dysfunctions may contribute to neurological and cardiovascular conditions, alongside cancer.
“The genome experiences a kind of ‘stirring’ due to the motions of genes driven by transcription,” states Alexandra Zidovska, a physics professor at New York University and the leading author of the research. “The movement of genes varies depending on whether they are being transcribed, leading to complex, turbulent-like motions within the human genome. Understanding the mechanics of these transcription-driven movements in the nucleus may be crucial for comprehending the human genome’s role in health and disease.”
The human genome spans two meters (about six and a half feet) of DNA, all compacted within a cell nucleus that measures just 10 micrometers in diameter, which is roughly 100,000 times smaller than the genome’s total DNA length. The DNA carries instructions for cellular processes and functions, with genes acting as basic units of this information. Different genes are accessed and processed at different times, and when a gene is being transcribed, molecular machinery interacts with it to convert its instructions into an mRNA molecule, in a process called transcription.
Zidovska and her team had previously identified significant “stirring” or movement of the genome, which results in its reorganization and repositioning within the nucleus.
However, the underlying cause of these movements remains largely unclear. Scientists have speculated that molecular motors powered by adenosine triphosphate (ATP) molecules, which supply energy for various biological processes, are responsible for driving these motions. These active motors are presumed to exert forces on the DNA, causing movement in both the DNA and the fluid surrounding it, known as nucleoplasm. Yet, the overall physical mechanisms remain poorly understood.
With this context, Zidovska and her colleagues directed their attention to RNA polymerase II, the enzyme that facilitates transcription and is one of the most prevalent molecular motors in the nucleus. When a gene is actively transcribed, the necessary molecular machinery exerts forces on the DNA during this process.
The study in Nature Communications explored how the motion of a single actively transcribed gene influences the movements of the surrounding genome in live human cells. To achieve this, the authors employed CRISPR technology to fluorescently label individual genes, utilized two-color high-resolution live cell microscopy to track the movements of these labeled genes, and applied displacement correlation spectroscopy (DCS) to map the flows of the genome across the nucleus. The imaging data were subjected to physical and mathematical analysis, revealing a previously unseen physical picture of gene motions within the cell.
Initially, the researchers observed how genes behaved when inactive and then “turned on” these genes to monitor the changes in their movement once they became “active.” Concurrently, they utilized DCS to analyze the flows of the surrounding genome, observing how the genome’s dynamics changed before and after the activation of the genes.
The results showed that active genes actively contribute to the stirring motion of the genome. By simultaneously monitoring the movements of individual genes and the overall genome, the researchers found that the compactness of the genome influences the gene’s activity contributions. Specifically, the analysis indicated that an active gene stimulates genomic movements in less compact areas, while highly packed regions drive the gene’s movements regardless of its active or inactive status.
“By unveiling these unforeseen connections between gene activity, genome compaction, and genome-wide motions, these findings reveal critical aspects of the genome’s spatial and temporal organization that directly influence gene regulation and expression,” notes Zidovska.
This research also contributes to our broader understanding of physics.
“Our findings provide fresh insights into the physics of active, living systems,” she adds. “By uncovering emergent behaviors in active living systems such as the human genome, we expand our understanding of physics.”
Additional authors of the paper include Fang-Yi Chu and Alexis S. Clavijo, both doctoral students at NYU, and postdoctoral researcher Suho Lee.
This work was supported by grants from the National Institutes of Health (R00-GM104152 and R01-GM145924), the National Science Foundation (CAREER PHY-1554880, PHY-2210541, and CMMI-1762506), along with a New York University Whitehead Fellowship for Junior Faculty in Biomedical and Biological Sciences.
