Summary: For decades, biology textbooks have taught that DNA is either “on” (unwrapped and active) or “off” (tightly coiled around protein spools called nucleosomes). A new study has shattered this binary view.
Using a new AI-powered tool called IDLI, researchers discovered that nucleosomes are not frozen locks but dynamic “volume dials.” By identifying 14 distinct structural states of these DNA spools, the team revealed a sophisticated “organizational code” that allows cells to fine-tune gene activity with incredible precision.
Key Facts
- Beyond the Spool: Traditionally, nucleosomes were seen as static barriers. The new AI method, IDLI (Iteratively Defined Lengths of Inaccessibility), proved that over 85% of nucleosomes are actually distorted or “loose,” leaving sections of DNA partially accessible.
- 14 States of Activity: The researchers identified a “grammar” of 14 different structural shapes. Each state corresponds to a different level of gene activity, functioning more like a dimmer switch than a simple light switch.
- The AI Breakthrough: IDLI uses two-dimensional scanning, analyzing both the length of the DNA fiber and the internal structure of individual nucleosomes, to detect subtle distortions that previous technologies missed.
- Transcription Factors as Architects: Special proteins (transcription factors) don’t just find open DNA; they actively “muscle” nucleosomes into specific shapes to force genes to stay open or remain locked.
- Disease & Aging Relevance: Many complex diseases, like cancer and neurodegeneration, aren’t caused by broken genes but by “wrong volumes”, genes being read at 50% instead of 100%, or vice versa. Mapping these 14 states offers a new way to diagnose and potentially reverse these shifts.
Source: Gladstone Institute
Every cell in the human body squeezes over six feet of DNA into a miniscule speck invisible to the naked eye—like compressing a whole house into a single sugar cube. In order to fit in a cell and remain organized, DNA is carefully wrapped around spool-like protein clusters called nucleosomes.
For decades, the prevailing view held that DNA is coiled so tightly around a nucleosome that it’s basically locked away and the cell can’t access it. Scientists believed only unwrapped DNA could be active. Now, a study from Gladstone Institutes and the Arc Institute challenges that black-and-white view.
Using a new AI-powered computational method, scientists discovered that most nucleosomes contain sections of DNA that are partially accessible to the cell, rather than fully wound up and packed away.
The findings, published in the journal Nature, point to a previously unrecognized way that cells control their genes.
“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 Gladstone Investigator Vijay Ramani, PhD, one of the scientists who led the new study. “This is a completely new organizational code for the genome.”
A New Way to Read DNA Packaging
All cells in the body carry the same DNA, but different cells use only the genes relevant to their specific jobs. To achieve this, cells have elaborate systems for controlling which genes are accessible and which are stored away. Nucleosomes have long been considered one of the primary elements of this filing system.
This is why researchers often study chromatin—which is all of a cell’s DNA packaged using nucleosomes—to get a sense of what genes a cell is using.
The Ramani lab previously developed a technology called SAMOSA, which for the first time mapped where nucleosomes were located along individual DNA molecules. Their new tool, IDLI (Iteratively Defined Lengths of Inaccessibility), builds on that foundation using an AI model trained to recognize subtle differences between nucleosome structures within the SAMOSA sequencing data.
Rather than simply locating each nucleosome, IDLI scans the data in two dimensions—across the length of the DNA fiber and within each nucleosome itself—to probe its internal structure.
Beyond On and Off: A Dynamic View of Chromatin
Each nucleosome is made of eight distinct building blocks, and IDLI can detect whether all of those blocks are present and tightly bound to each other. Missing or loose building blocks indicate that the nucleosome is distorted, with sections of DNA partially exposed.
The scientists used their new tool to analyze the chromatin from mouse embryonic stem cells. They found that more than 85 percent of nucleosomes showed some degree of distortion.
“Our findings suggest that the genome is far more dynamic and accessible that the scientific community realized,” Ramani says.
Crucially, the team showed that the DNA distortions are not random, but carefully programmed by the cell. They identified 14 distinct structural states of nucleosomes, each associated with different levels of gene activity. The same patterns appeared in human stem cells being coaxed into liver-like cells, and in liver cells taken directly from mice.
For Hani Goodarzi, PhD, an investigator at the Arc Institute who led the study with Ramani, the findings represent a fundamental shift in how scientists should think about chromatin.
“Before this, our understanding of chromatin was a bit like reading a text that only had sound and silence—just two states of being,” Goodarzi says. “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 team also showed that transcription factors, which are special proteins responsible for turning genes on and off, directly shape those nucleosome structures. When the researchers removed two of these proteins from cells, the nucleosome distortion patterns shifted in predictable ways. The findings suggest that transcription factors are responsible for forcing nucleosomes to either stay open or remain locked.
“This adds to the many different ways in which a cell can tune things up and down, by making parts of the DNA more or less accessible,” says Ramani.
Mapping a Path Toward Healthier Aging
For many complex conditions, scientists have not been able to pinpoint specific DNA changes that trigger disease. That’s likely because diseases like cancer and neurodegeneration arise from small shifts across many genes at once—genes that should be completely off instead being read by the cell, or vice versa.
Ramani sees the 14 new nucleosome states as a kind of readout for those shifts.
“These are precisely the states that end up being quite important in terms of disease relevance,” says Ramani. “Most complex diseases revolve around gradation; maybe a gene is on but at half the level it would normally be, or maybe it’s on in the wrong cell type.”
The researchers also see promise in applying the new tool to aging research. Chromatin structure changes in predictable ways as cells age, and some of those changes appear to be reversible. Ramani envisions using IDLI to map how nucleosome states shift across different tissues during aging.
Those kinds of studies could eventually point toward therapeutics that restore healthy nucleosome patterns in aging or disease.
“We’re reading the language, but ultimately, we want to learn how to speak it so that we can control and modify it,” Goodarzi says. “We’re not here just to observe biology; at some point we want to intervene.”
About the Study
Funding: The work was supported by the National Institutes of Health (T32-DK060414, U01-DK127421, DP2-HG012442), the California Institute for Regenerative Medicine, the Searle Scholars Program, and the W.M. Keck Foundation.
Key Questions Answered:
A: Not necessarily. Think of it as a book that is slightly cracked open instead of slammed shut. The gene is available to be read, but the cell still needs the right “readers” (proteins) to come along. This partial access allows the cell to respond much faster to changes than if it had to unspool the DNA entirely.
A: Researchers used a technology called SAMOSA to map DNA molecules. The AI was then trained to recognize patterns in the “accessibility” data. If a nucleosome was missing a building block or was loosely bound, the AI detected a specific “signature” of exposed DNA that shouldn’t be there in a “perfect” spool.
A: That is the ultimate goal. Chromatin structure (how DNA is packed) degrades in very predictable ways as we age. By mapping the healthy “nucleosome grammar” of a young cell, scientists hope to develop therapies that can “re-spool” the DNA of older cells back into a youthful, healthy state.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics research news
Author: Kelly Quigley
Source: Gladstone Institutes
Contact: Kelly Quigley – Gladstone Institutes
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Pervasive and programmed nucleosome distortion on single chromatin fibres” by Marty G. Yang, Hannah J. Richter, Simai Wang, Colin P. McNally, Camille M. Moore, Ali Emadi, Nicole E. Harris, Simaron Dhillon, Michela Maresca, Huimin Pan, Hayden Saunders, Ruiqiao Yang, Megan S. Ostrowski, Erika C. Anderson, Elzo de Wit, Jacquelyn J. Maher, Yuhong Fan, Geeta J. Narlikar, Elphège P. Nora, Holger Willenbring, Hani Goodarzi & Vijay Ramani. Nature
DOI:10.1038/s41586-026-10418-6
Abstract
Pervasive and programmed nucleosome distortion on single chromatin fibres
Despite decades of biochemical and structural studies of the nucleosome, researchers lack genome-scale methods to determine variability in nucleosome structure along individual chromatin fibres. T
o address this, here we present Iteratively Defined Lengths of Inaccessibility (IDLI), a computational method that maps the single-molecule co-occupancy of structurally distinct nucleosomes, subnucleosomes and other protein–DNA interactions through long-read single-molecule footprinting.
IDLI classifies methylase-inaccessible footprints on individual chromatin fibres into (i) linker-histone-associated nucleosomes; (ii) nucleosomes with focal DNA accessibility along the nucleosome wrap; (iii) unwrapped nucleosomes; and (iv) subnucleosomal species such as hexasomes, tetrasomes and other short DNA protections. Applying IDLI to chromatin from mouse embryonic stem cells, we discover that more than 85% of nucleosomes exhibit intranucleosomally accessible DNA (nucleosome ‘distortion’).
We observe epigenomic-domain- and expression-level-specific patterns of distortion, including at promoters and mouse satellite repeat sequences. Transcription factor (TF) motif occurrence correlates significantly with distinct types of distortion, and degron experiments provide evidence of direct regulation by TFs. We apply IDLI to in vitro endoderm differentiation in human induced pluripotent stem cells and primary mouse hepatocytes.
In both cases, we observe distortion at pioneer TF FOXA2 binding sites, demonstrating that distortion is developmentally encoded and present in vivo. Finally, genetic experiments in mice show that a nucleosome-binding domain of FOXA2 directly affects nucleosome structure in vivo, implicating these protein–nucleosome interactions as direct mediators of distortion. Our work suggests extreme but regulated nucleosome structural variability at the single-molecule level.
Furthermore, our approach offers opportunities to model TF binding, nucleosome remodelling and cell-type-specific chromatin regulation across biological contexts.
