Unraveling the Mechanics Behind Transcription-Dependent Motions of Single Genes

A group of researchers has found unexpected links between genome packing, gene activity, and genome-wide motions, exposing features of the genome's structure that have a direct impact on gene expression and regulation.

The results, published in the journal Nature Communications, advance the knowledge of the mechanisms underlying transcription-dependent movements of individual genes, the malfunction of which can result in cancer, neurological conditions, and cardiovascular diseases.

The genome is ‘stirred’ by transcription-driven motions of single genes. 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.”

Alexandra Zidovska, Professor and Study Senior Author, Department of Physics, New York University

Around 2 m (six and a half feet) of DNA that make up the human genome are contained within a nucleus that is only 10 micrometers in diameter, which is 100,000 times smaller than the DNA's length. Genes are information units, and the DNA molecule encodes information for all cellular functions and processes.

Information from various genes is processed at different moments after they are read. Transcription is the process by which biological machinery accesses a gene during reading and converts its information into an mRNA molecule.

Zidovska and her colleagues had previously found that the genome is constantly “stirred,” or moved, which causes it to reorganize and realign itself within the nucleus.

However, little is known about the genesis of these motions. Researchers have theorized that the drivers are molecular motors powered by adenosine triphosphate (ATP) molecules, which supply energy for a variety of biological functions.

It is believed that these active motors exert forces on DNA, which may cause DNA and the fluid surrounding it, the nucleoplasm, to move. However, the more extensive physical mechanisms behind it are still unknown.

Since RNA polymerase II is one of the most prevalent molecular motors in the cell nucleus and is in charge of transcription, Zidovska and her colleagues concentrated on it. The responsible molecular machinery exerts stresses on DNA during its processing when a gene is active, or actively transcribed.

The study examined the effects of a single, actively transcribed gene on the movements of the surrounding genome in living human cells. To accomplish this, the researchers used displacement correlation spectroscopy (DCS) to concurrently map genome flows across the nucleus, two-color high-resolution live cell imaging to monitor the motion of these labeled genes, and CRISPR technology to fluorescently label individual genes.

Following a physical and mathematical study of the high-resolution imaging data, a hitherto unobserved physical image of the movement of genes within cells was revealed.

The researchers first looked at how the genes moved while they were not in use, then they “switched” the genes on and saw how their movements changed when they were “active.” In parallel, they employed DCS to map the surrounding genome's flows, tracking the genome's movement across the nucleus both before and after gene activation.

Overall, the researchers discovered that the stirring motion of the genome is facilitated by activated genes. They demonstrate that the compaction of the genome influences the contribution of the gene by mapping single-gene and genome-wide movements simultaneously.

In low-compaction regions, a single active gene drives the genome's motions, according to a motion-correlation analysis; in high-compaction regions, however, gene motion is driven by the genome independent 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.”

Alexandra Zidovska, Professor and Study Senior Author, Department of Physics, New York University

This study expands current knowledge in the field of physics.

This research provides new insights into the physics of active and living systems. By revealing an emergent behavior of active living systems, such as the human genome, it teaches us new physics.”

Alexandra Zidovska, Professor and Study Senior Author, Department of Physics, New York University

Motion of a single gene (white dot) is marked by its trajectory (colored curve) within the flows of the surrounding genome (arrows). Video Credit: Image courtesy of Alexandra Zidovska, Department of Physics, New York University