Recently, a research team led by Professor Li Hui from the School of Systems Science at Beijing Normal University, in collaboration with Institute of Physics, Chinese Academy of Sciences and Southern Medical University, published their findings in Nature Communications. The study reveals for the first time that extracellular osmotic pressure can dynamically modulate the labelling efficiency at specific genomic loci and regulate gene transcriptional activity by modulating intranuclear crowding, thereby exerting an on-off-like control effect. From a physical perspective, this discovery uncovers a previously unrecognized regulatory route through which environmental cues cross the cellular boundary and act directly on the nucleus, the cell’s command center, providing a key clue to understanding how living systems sense and respond to the physical environment.

The abstract of this paper is as follows:

Extracellular osmotic pressure is a key modulator of intracellular biophysical properties and cellular functions. However, its impact on the cell nucleus remains elusive, largely due to the challenges in real-time measurement of local environmental properties and reaction kinetics at specific loci within the nucleus. Here, we employ the dCas9-SunTag system to investigate the biophysical response at target DNA loci to osmotic pressure alterations. We reveal that variations in extracellular osmotic pressure modulate the efficiency of dCas9-SunTag-mediated fluorescent labelling rapidly and reversibly, with hypoosmotic condition increasing and hyperosmotic condition decreasing the number and fluorescence intensity of foci for telomeres and genes. Strikingly, osmotic pressure also regulates gene transcription with the dCas9-SunTag system, mirroring its effects on fluorescent labelling, as evidenced by changes in mRNA burst frequency. The underlying mechanism is that osmotic pressure shifts the binding-unbinding equilibrium of specific proteins to dCas9-SunTag complex by altering intranuclear crowding. These findings not only highlight the role of mechanical cues in modulating DNA-related processes within the nucleus, but also establish the dCas9-SunTag system as a sensitive probe for intranuclear crowding in response to extracellular cues, notably osmotic pressure.

Reference: https://doi.org/10.1038/s41467-025-66160-6