DNA inside the nucleus is not packed as a rigid regular fiber—linker histone H1 dynamically binds and loosely "glues" nucleosomes together, creating a dynamic, fluid organization that can still support essential genome functions.
The human genome has a remarkable capacity for compaction. If all 46 human chromosomes were stretched end to end, they would collectively reach about two meters in length, yet they are somehow arranged within a nucleus only ~10 micrometers in diameter. To fit inside the nucleus, DNA is wrapped around histone proteins, like thread around a spool, to form nucleosomes. Nucleosomes and associated proteins then fold into chromatin, enabling the genome to be packaged while remaining functional.
For decades, molecular biology textbooks described linker histone H1 as a key factor that organizes nucleosomes into regular, rigid higher-order structures (often depicted as a 30-nm chromatin fiber). However, accumulating evidence suggests that such highly ordered fibers are very rare in living cells. This raises a fundamental question: how does H1 actually compact DNA and organize chromatin in vivo?
A team led by Professor Kazuhiro Maeshima at SOKENDAI and the National Institute of Genetics (Research Organization of Information and Systems, ROIS) in Japan and Professor Rosana Collepardo-Guevara at the University of Cambridge in U.K. investigated how H1 binds to nucleosomes and shapes chromatin inside living human cells. By combining single-nucleosome imaging with super-resolution fluorescence microscopy and computational modeling, the researchers reveal a new physical picture of H1 function: rather than working as a static clamp (see Figure, left), H1 behaves like a dynamic, liquid-like "glue" that gently folds chromatin into a fluid organization that remains accessible to other molecules (Figure, right).
The team published their results in Science Advances on [April 8, 2026].
DOI: 10.1126/sciadv.aec9801
http://www.science.org/doi/10.1126/sciadv.aec9801
"Our results show that H1 is not simply a 'static clamp' that locks chromatin into a rigid fiber," said Maeshima. "Instead, H1 dynamically associates with nucleosomes and acts more like a liquid-like glue—helping chromatin condense while maintaining a dynamic, adaptable organization."
To observe chromatin at the scale of individual nucleosomes in living cells, the team used a strategy that labels nucleosomes sparsely with fluorescence, enabling super-resolution localization and motion tracking (see the video). The experiments revealed that H1-mediated chromatin condensation can be achieved without forming highly ordered, stiff fibers.
"By tracking nucleosomes in living cells at high spatial resolution, we could directly test whether chromatin behaves like a rigid structure or something more dynamic," said Masa A. Shimazoe. "What we see is a condensed but fluid organization—consistent with H1 binding and unbinding in a highly dynamic way."
To connect the imaging observations to an underlying physical mechanism, the researchers developed coarse-grained models of chromatin. Using near-atomistic molecular dynamics (MD) simulations, they evaluated how H1–chromatin interactions would affect compaction, organization, and dynamics.
"Our simulations let us zoom in and uncover the microscopic rules by which H1 shapes chromatin," said Rosana Collepardo-Guevara and Jan Huertas. "We were very excited when we saw why H1 acts as a dynamic, liquid-like glue: by forming multivalent interactions between multiple nucleosomes, H1 builds a flexible network that holds chromatin together without locking it into a rigid structure. This shows how small changes in H1 can propagate to reshape the genome at larger scales."
Because genome function requires large protein assemblies to access DNA—for transcription, replication, and repair—the researchers propose that a liquid-like chromatin organization is advantageous: chromatin can remain compact while still allowing other molecular machines to penetrate and operate.
"Understanding the physical nature of chromatin in living cells is essential for explaining how the genome is read, copied, and maintained," said Maeshima. "This work provides a new conceptual model for H1, and it may help us understand how abnormal H1 function contributes to genome dysregulation and disease."
Other contributors include Masa A. Shimazoe, Satoru Ide, and Sachiko Tamura from the Genome Dynamics Laboratory, National Institute of Genetics (ROIS) in Mishima, Japan (M.A. Shimazoe, S. Ide also belong to SOKENDAI in Mishima; S. Ide is presently at the Cell Biology Center, Institute of Integrated Research, Institute of Science Tokyo in Yokohama); Jan Huertas, Charles Phillips, and Stephen Farr from the University of Cambridge in Cambridge, UK (Departments of Chemistry and Genetics); S. S. Ashwin from Gandhi Institute of Technology and Management (GITAM) University in Bengaluru, India; and Masaki Sasai from Kyoto University in Kyoto, Japan.
This research was supported by Japan Society for the Promotion of Science (JSPS) and MEXT KAKENHI grants JP23K17398, JP24H00061, JP22H00406, JP21H02535, and JP22H05606; the Takeda Science Foundation; the UK Government's Guarantee scheme (EP/Z002028/1) following funding from the European Research Council (Consolidator Grant); the UK High-End Computing Consortium for Biomolecular Simulation (EP/R029407/1); the Herchel Smith Postdoctoral Fellowship; UK Research and Innovation (UKRI) Postdoctoral Fellowships Guarantee scheme (EP/X02332X/1); JSPS Research Fellowship JP24KJ1161; and the National Institute of Genetics 2023 NIG-JOINT (4I2023).
