Every human cell compacts more than six feet of DNA into a microscopic space by wrapping it around protein complexes known as nucleosomes. This packaging system has long been thought to tightly coil DNA, making it inaccessible unless fully unwrapped. Under that traditional model, gene activity depended on whether DNA was either exposed or completely hidden.
A study from Gladstone Institutes and the Arc Institute challenges this binary view. Using an AI-driven computational approach, researchers found that most nucleosomes contain DNA regions that remain partially accessible, suggesting gene regulation operates along a continuum rather than a simple on-or-off mechanism. The findings, published in Nature, introduce a different way of understanding genome organization.
“The conception before was that, when it came to nucleosomes, genes were either turned on or off, but we’re finding it’s more like a volume dial,” says senior author Vijay Ramani. “This is a completely new organizational code for the genome.”
To investigate chromatin structure in greater detail, the team built on a previous sequencing method called SAMOSA, which mapped nucleosome positions along individual DNA strands. Their new tool, IDLI (Iteratively Defined Lengths of Inaccessibility), uses AI to detect subtle structural differences within nucleosomes by analyzing sequencing data across both DNA length and internal nucleosome features.
Each nucleosome consists of eight protein subunits. IDLI can determine whether these components are intact and tightly assembled or partially disrupted. When subunits are missing or loosely arranged, sections of DNA become exposed. Applying this method to mouse embryonic stem cells revealed that more than 85 percent of nucleosomes exhibited some level of distortion.
Importantly, these distortions were not random. The researchers identified 14 distinct nucleosome structural states, each linked to varying levels of gene activity. Similar patterns were observed in human stem cells differentiating into liver-like cells and in mature mouse liver cells.
“Before this, our understanding of chromatin was a bit like reading a text that only had sound and silence—just two states of being,” says co-senior author Hani Goodarzi. “Now we can see that it’s much more nuanced. There are letters and words, and we uncovered a new kind of grammar that controls them.”
The study also showed that transcription factors actively shape nucleosome structure. Removing two such proteins altered nucleosome configurations in predictable ways, indicating their role in modulating DNA accessibility.
These findings may help explain diseases driven by subtle gene regulation changes. Rather than single mutations, many conditions involve shifts in gene activity levels. The identified nucleosome states could serve as indicators of these changes and may also inform studies of aging, where chromatin structure evolves over time.
Publication details: Yang, M.G., Richter, H.J., Wang, S. et al. Pervasive and programmed nucleosome distortion on single chromatin fibres. Nature (2026). https://doi.org/10.1038/s41586-026-10418-6
A study from Gladstone Institutes and the Arc Institute challenges this binary view. Using an AI-driven computational approach, researchers found that most nucleosomes contain DNA regions that remain partially accessible, suggesting gene regulation operates along a continuum rather than a simple on-or-off mechanism. The findings, published in Nature, introduce a different way of understanding genome organization.
“The conception before was that, when it came to nucleosomes, genes were either turned on or off, but we’re finding it’s more like a volume dial,” says senior author Vijay Ramani. “This is a completely new organizational code for the genome.”
To investigate chromatin structure in greater detail, the team built on a previous sequencing method called SAMOSA, which mapped nucleosome positions along individual DNA strands. Their new tool, IDLI (Iteratively Defined Lengths of Inaccessibility), uses AI to detect subtle structural differences within nucleosomes by analyzing sequencing data across both DNA length and internal nucleosome features.
Each nucleosome consists of eight protein subunits. IDLI can determine whether these components are intact and tightly assembled or partially disrupted. When subunits are missing or loosely arranged, sections of DNA become exposed. Applying this method to mouse embryonic stem cells revealed that more than 85 percent of nucleosomes exhibited some level of distortion.
Importantly, these distortions were not random. The researchers identified 14 distinct nucleosome structural states, each linked to varying levels of gene activity. Similar patterns were observed in human stem cells differentiating into liver-like cells and in mature mouse liver cells.
“Before this, our understanding of chromatin was a bit like reading a text that only had sound and silence—just two states of being,” says co-senior author Hani Goodarzi. “Now we can see that it’s much more nuanced. There are letters and words, and we uncovered a new kind of grammar that controls them.”
The study also showed that transcription factors actively shape nucleosome structure. Removing two such proteins altered nucleosome configurations in predictable ways, indicating their role in modulating DNA accessibility.
These findings may help explain diseases driven by subtle gene regulation changes. Rather than single mutations, many conditions involve shifts in gene activity levels. The identified nucleosome states could serve as indicators of these changes and may also inform studies of aging, where chromatin structure evolves over time.
Publication details: Yang, M.G., Richter, H.J., Wang, S. et al. Pervasive and programmed nucleosome distortion on single chromatin fibres. Nature (2026). https://doi.org/10.1038/s41586-026-10418-6