Mechanism of Cohesin Ring Fluidity Suppression and Transcriptional Insulation Revealed via Ultra-High-Resolution Single-Molecule Tracking
Background
How the genome folds in 3D space within the cell nucleus is a key mechanism determining gene expression regulation. Human cells must precisely compress approximately 2 meters of deoxyribonucleic acid (DNA) into a nucleus only a few micrometers in diameter. In this process, euchromatin regions, where transcription is active, must maintain an open structure to allow easy access for the transcriptional complex. Simultaneously, they bear the responsibility of forming physical boundaries to prevent neighboring genes from interacting indiscriminately.
In the academic community, the ring-shaped protein complex cohesin has been understood to establish the boundaries of topologically associating domains (TADs) by pushing DNA strands to form loops. However, existing analysis methods such as Chromatin Conformation Capture (Hi-C) were limited to showing the average state of millions of cells. Because of this population-based measurement approach, it was difficult to reveal how cohesin controls chromatin nanostructures in real-time within individual cells. Regarding the cause of transcriptional insulation breakdown when cohesin is deficient, it remained unclear whether it was due to changes in the condensation volume of the entire chromatin or changes in the dynamic properties of its internal components.
Key Findings
Researchers combined ultra-high-resolution three-dimensional structured illumination microscopy (3D-SIM) and single-nucleosome tracking (SNT) techniques to capture true euchromatin regions in living cells at the molecular level. This was achieved by precisely recording the local behavior of chromatin by tracking the trajectories of individual nucleosomes through high-speed imaging at dozens of frames per second.
Observations revealed that the loops formed by cohesin act as molecular anchors to prevent condensed heterochromatic domains from shaking. When the researchers rapidly depleted cohesin using chemical-induced degradation technology, an unexpected physical response was observed. While the overall volume or condensation density of the euchromatic domains remained almost unchanged, the movement speed of individual nucleosomes and the fluidity within the domains surged sharply.
As internal fluidity increased without the overall shape unraveling, local domain mixing occurred, blurring the boundaries between adjacent chromatin domains. Nano-domains, having lost their fences, became entangled, causing adjacent areas that should have been separate to mix randomly. As the physical boundaries between domains collapsed, enhancers contacted incorrect promoters, leading to abnormal transcriptional interference. This moment revealed the physical principle that cohesin preserves gene insulation not by making chromatin more densely packed, but by constraining molecular fluctuations.
Significance and Outlook
This study opens a new paradigm of viewing the 3D spatial arrangement of the genome not as a static structure, but as a dynamic fluid property. This is because it clearly demonstrates that the boundaries regulating gene expression arise from the failure of microscopic fluidity control rather than macroscopic structural collapse.
These findings provide important clues for elucidating the pathological mechanisms of diseases caused by abnormalities in the cohesin complex. It becomes possible to explain why cohesin mutations, observed in congenital developmental diseases like Cornelia de Lange syndrome or in patients with acute myeloid leukemia, cause fatal transcriptional disturbances even without massive chromosomal structural abnormalities. In essence, the fundamental cause of gene expression disorders can be traced to the disruption of molecular dynamics.
Challenges clearly remain. Since this observation was limited to euchromatic regions with high transcriptional activity, additional verification is needed to see if the same molecular dynamics apply to tightly packed heterochromatin. Furthermore, the development of next-generation bio-imaging technologies capable of precisely observing such nanometer-scale dynamic mixing in actual living tissue environments, beyond cultured cells, is expected to follow.
Nature Genetics, Published online: 08 September 2026; doi:10.1038/s41588-026-02736-2Single-nucleosome imaging/tracking and super-resolution three-dimensional structured illumination microscopy within euchromatic regions show that cohesin-mediated loops constrain condensed euchromatic domains. Cohesin loss increases their fluidity without affecting their overall compaction, leading to local domain mixing and compromised transcriptional insulation.
This discovery provides an opportunity to reshape drug development strategies for intractable blood cancers and rare genetic diseases accompanied by cohesin gene mutations. While past approaches focused on restoring abnormal chromatin condensation, future approaches can enable targeted interventions to control local fluidity within domains or block abnormal mixing between adjacent regions.
Specifically, patient cells with STAG2 deletions, which frequently occur in acute myeloid leukemia, can be targeted. A promising scenario is the screening of small-molecule compounds to selectively block the transcriptional proximity contacts of primary oncogenes that are abnormally activated due to domain mixing in these cells. Additionally, by introducing single-nucleosome tracking technology as a drug efficacy screening platform, a new drug evaluation metric can be established to directly determine whether chromatin fluidity is normalized after treatment with candidate compounds.