How Chromatin Moves to Shape Gene Expression

MIT researchers measured chromatin movement across an exceptionally wide range of timescales, from hundreds of microseconds to hours, and used those measurements to better define how chromatin behaves inside the nucleus. The study shows that chromatin does not move in a single uniform way. Instead, it appears to fall into two broad categories: one in which motion is tightly constrained and mostly keeps chromatin in contact with nearby genomic regions, and another in which chromatin can move more freely and reach farther regions, but only over longer periods of time.

The work helps clarify how gene expression is regulated because chromatin movement affects how genes interact with regulatory elements such as enhancers. It also has implications for other nuclear processes, including DNA repair, where broken DNA ends need to come together.

“Because we were able to look at chromatin dynamics for the first time at these very fast timescales, and also for the first time across the full dynamic range, we were able to observe chromatin motion over a range that just wasn’t possible before,” says Anders Sejr Hansen, senior author of the new study published in Nature Structural and Molecular Biology.

A major advance in the study was the use of MINFLUX, a super-resolution microscopy technique that allowed the team to observe chromatin motion faster and for longer than conventional imaging methods could manage. The researchers were the first to apply this technique to chromatin in living cells. By combining MINFLUX with two traditional imaging approaches, they tracked chromatin across seven orders of magnitude in time, from hundreds of microseconds to several hours. They used mouse and human cell types to build a more statistically robust picture of chromatin behavior.

One important result was the identification of a “region of influence” around a genomic locus. Within roughly a couple hundred nanometers, loci appear to remain effectively in contact over short and intermediate timescales. This means that nearby genomic regions can routinely find one another through normal chromatin motion. The researchers also suggest that genes and regulatory elements within about 100,000 base pairs do not need extra assistance to interact, because they can encounter each other within milliseconds or minutes, a timescale consistent with transcription.

The second class of behavior involves broader chromatin movement that occurs only over minutes to hours and was seen in some cell types but not others. The reasons for that variation remain unclear. The findings also suggest that existing models of chromatin dynamics do not fully explain the strength of the subdiffusive pull observed in the study, indicating that those models may need to account for additional factors, including interactions with the crowded nucleoplasm.