DNA Folding and Protein Accumulation Drive Gene Activity Bursts

Researchers at Kyushu University have published new insights into the mechanisms behind transcriptional bursting, a key process in gene expression. Using seq-DNA/RNA-IF-FISH and computer modeling, the team revealed how the spatial organization of DNA and protein accumulation influence gene activity in mouse embryonic stem cells.

The study focused on the Nanog gene, known for its transcriptional bursting behavior. When the gene was active, researchers observed that distant enhancer regions were in close proximity to the gene's promoter. Conversely, these enhancers were physically farther away when the gene was inactive.

Additionally, the scientists also found that proteins involved in regulating transcription also accumulated in the area around the enhancers and promoters when Nanog was active.

To better understand the mechanism, Professor Hiroshi Ochiai, senior author of the study published in Science Advances, and his team used computer modeling to simulate how the different parts of DNA interact and move inside the cell, both when the Nanog gene is active and inactive.

They developed their model by using data from their imaging experiments to make a “map” of how frequently different regions of DNA interacted with each other and how the DNA was folded in space. Using this map, the model then simulated how the DNA chain might randomly move.

The model predicted that when in the active state, each enhancer region interacted for more than twice as long with the promoters, compared to when the gene was inactive.

The model showed that these longer periods of interaction occurred due to “friction” around the DNA. Due to the accumulation of proteins and RNA when Nanog was active, the fluid became more viscous, and caused the modelled DNA strand to move slowly.  Therefore, the gene was able to stay active for longer bursts of time. In contrast, the simulated DNA moved quicker when Nanog was inactive, meaning that the promoter and enhancers didn’t have time to interact.

“The modeling suggests that bursting is stabilized due to these reinforcing loops,” concluded Ochiai. “Of course, this is just a simulation. The next step is to prove this mechanism also occurs in cells.”

These findings could have implications for understanding diseases caused by improper gene regulation and may lead to new therapeutic approaches.