Some of the incredible complexity underlying the genome is understood. For example, the effects of chromatin remodeling on gene expression. However, the implications of the movements that occur during chromatin remodeling are largely not understood.

New work has uncovered connections between those genome-wide motions, gene activity, and genome packing. The findings reveal aspects of the genome’s organization that directly affect gene regulation and expression. In doing so, it bolsters our understanding of the mechanics behind transcription-dependent motions of single genes—the dysfunction of which may lead to neurological and cardiovascular disorders as well as cancer.

“The genome is ‘stirred’ by transcription-driven motions of single genes,” explained Alexandra Zidovska, PhD, a professor of physics at New York University. “Genes move differently, depending on whether they are being read or not, leading to complex, turbulent-like motions of the human genome. Understanding the mechanics behind transcription-dependent motions of single genes in the nucleus might be critical for understanding the human genome in health and disease.”

The findings are reported in Nature Communications in the paper, “Transcription-dependent mobility of single genes and genome-wide motions in live human cells.”

It had previously been discovered that the genome undergoes a lot of “stirring,” or movement, leading to its reorganization and repositioning in the nucleus. Here, the researchers investigated, in live human cells, how the motion of a single actively transcribed gene affects the motions of the genome around it.

To do so, they performed simultaneous mapping of single-gene and genome-wide motions.  They used CRISPR to fluorescently label single genes, two-color high-resolution live cell microscopy to visualize the motion of these labeled genes, and displacement correlation spectroscopy (DCS) to simultaneously map flows of the genome across the nucleus. The high-resolution imaging data were then processed through a physical and mathematical analysis, uncovering a never-before-seen physical picture of how genes move inside the cell.

Motion of a single gene (white dot) is marked by its trajectory (colored curve) within the flows of the surrounding genome (arrows). [Alexandra Zidovska, Department of Physics, NYU]

In their study, the researchers initially examined the motions of the genes in both active and inactive states. At the same time, the authors used DCS to map flows of the surrounding genome, monitoring how the genome flows across the nucleus before and after gene activation.

Overall, the authors found that active genes contribute to the stirring motion of the genome. Through simultaneous mapping of single-gene and genome-wide motions, they reveal that the compaction of the genome affects how the gene is contributing. Specifically, a motion-correlation analysis indicated that a single active gene drives the genome’s motions in low-compaction regions, but a high-compaction genome drives gene motion regardless of its activity state.

“By revealing these unexpected connections among gene activity, genome compaction, and genome-wide motions, these findings uncover aspects of the genome’s spatiotemporal organization that directly impact gene regulation and expression,” said Zidovska.

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