Summary: For decades, textbooks taught that DNA is either “on” (unwrapped and accessible) or “off” (tightly wrapped on protein spools called nucleosomes). New research overturns this binary view, revealing a complex, programmable spectrum of nucleosome states that tune gene activity like a volume dial.
Using a novel AI-powered method named IDLI (Iteratively Defined Lengths of Inaccessibility), researchers found that nucleosomes are far from static barriers. Instead, they adopt a variety of distorted conformations that leave parts of the DNA partially exposed. By classifying 14 distinct nucleosome states, the team uncovered an organizational code that enables precise control of gene expression.
Key Facts
- Beyond the Spool: Nucleosomes were long viewed as rigid, inaccessible units. IDLI shows that over 85% of nucleosomes are distorted or loosened, making segments of DNA partially accessible.
- 14 Structural States: The study defines 14 reproducible nucleosome shapes, each linked to specific levels of gene activity—analogous to a dimmer rather than a simple on/off switch.
- AI-Driven Detection: IDLI combines long-read single-molecule footprinting with machine learning to analyze both the length of DNA fibers and the internal structure of individual nucleosomes, revealing subtle variations earlier methods missed.
- Transcription Factors Shape Structure: Transcription factors do more than seek open DNA; they actively remodel nucleosomes into particular shapes that promote or block gene reading.
- Disease and Aging Implications: Many complex disorders may arise from modest shifts in gene activity levels rather than gene mutations. Mapping these 14 nucleosome states offers a new approach to detect and potentially correct such misregulation.
Source: Gladstone Institute
Every human cell compacts more than six feet of DNA into a microscopic nucleus. To organize and protect this information, the genome is wrapped around protein cores called nucleosomes, which act like spools.
Traditionally, researchers assumed that DNA wrapped tightly on a nucleosome was effectively inaccessible, while unwrapped DNA was accessible and active. A collaborative study from Gladstone Institutes and the Arc Institute challenges that simple dichotomy.
Applying AI to high-resolution single-molecule data, the team found that many nucleosomes are partially unwrapped or otherwise distorted, leaving stretches of DNA accessible without fully exposing the entire nucleosomal wrap. These patterns point to a previously unrecognized layer of gene regulation.
The findings, published in the journal Nature, describe how cells use controlled, structural variation in nucleosomes to modulate genes with fine granularity.
“Previously we thought nucleosomes were either closed or open. Our work shows they function more like a volume dial,” says Gladstone Investigator Vijay Ramani, PhD. “This reveals a new organizational code for chromatin.”
A New Way to Read DNA Packaging
All cells have the same genome but activate different genes depending on their role. Chromatin—the DNA–protein assembly built from nucleosomes—is central to deciding which genes are available to be read. The Ramani lab earlier developed SAMOSA, a technique that maps nucleosome positions on single DNA molecules. Building on SAMOSA, IDLI uses machine learning to recognize structural differences within those mapped nucleosomes.
Unlike methods that only locate nucleosomes, IDLI examines two dimensions: the sequence length along each DNA fiber and the internal pattern of accessibility within every nucleosome. This enables detection of missing or loosened nucleosome components that expose DNA patches in characteristic ways.
Beyond On and Off: A Dynamic View of Chromatin
A nucleosome is composed of multiple histone proteins. IDLI can determine whether all histone subunits are tightly bound or whether some components are absent or loosely associated. Such distortions create reproducible accessibility signatures.
Analyzing chromatin from mouse embryonic stem cells, the researchers observed that more than 85% of nucleosomes displayed some intranucleosomal accessibility. Importantly, these distortions were not random: the team identified 14 distinct structural states, each associated with different gene expression patterns. These states were consistent across experimental systems, including human stem cells differentiating toward liver-like cells and primary mouse liver cells.
“Chromatin is far more dynamic and intricate than previously appreciated,” Ramani says. “We can now read patterns that resemble a language or grammar governing gene regulation.”
The study also demonstrates that specific transcription factors directly influence nucleosome distortion. Removing certain transcription factors shifted nucleosome states in predictable ways, supporting a model in which these proteins actively sculpt chromatin architecture to control gene activity.
Mapping a Path Toward Healthier Aging
Many complex diseases and age-related declines do not trace to single gene mutations but to subtle, widespread changes in how genes are expressed. Small shifts in expression—genes operating at half their normal level or being read in inappropriate cell types—can have large biological consequences. The 14-state nucleosome map provides a new readout for these graded changes.
Because chromatin structure changes predictably with age, IDLI could be used to chart how nucleosome states shift across tissues over time. That information may guide strategies to restore youthful chromatin patterns and intervene in disease processes.
“We aim not only to read this chromatin language but ultimately to learn how to modulate it,” says Hani Goodarzi, PhD, co-leader of the study. “Understanding these structural states opens paths for therapeutic intervention.”
About the Study
Funding: 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. Partial accessibility makes a gene available for reading, but the cell still requires specific proteins (transcription factors and other cofactors) to initiate transcription. This intermediate state allows rapid responses without fully unwrapping the nucleosome.
A: The researchers used SAMOSA to generate single-molecule accessibility maps and trained an AI model to recognize characteristic signatures of partial DNA exposure. The model distinguishes intact nucleosome footprints from those missing subunits or showing focal accessibility along the wrap.
A: That is a long-term goal. Because chromatin changes accompany aging in systematic ways, mapping healthy nucleosome patterns in young cells could inform therapies to restore aged cells toward a healthier state.
Editorial Notes:
- Edited by a Neuroscience News editor.
- The journal article was reviewed in full by staff.
- Additional context added by editorial staff.
About this genetics research news
Author: Kelly Quigley
Source: Gladstone Institutes
Contact: Kelly Quigley – Gladstone Institutes
Image: Image credit: Neuroscience News
Original Research: Open access. “Pervasive and programmed nucleosome distortion on single chromatin fibres” by Marty G. Yang et al., published in Nature. DOI: 10.1038/s41586-026-10418-6
Abstract
Pervasive and programmed nucleosome distortion on single chromatin fibres
Despite extensive biochemical and structural studies, methods for assessing nucleosome structural variability along individual chromatin fibres at genome scale have been limited. To address this, the authors developed IDLI, a computational approach that maps structurally distinct nucleosomes, subnucleosomes, and other protein–DNA interactions using long-read single-molecule footprinting.
IDLI classifies methylase-inaccessible footprints into several categories: linker-histone-associated nucleosomes, nucleosomes with focal accessibility along the wrap, unwrapped nucleosomes, and subnucleosomal particles such as hexasomes and tetrasomes. Applied to mouse embryonic stem cell chromatin, IDLI revealed that over 85% of nucleosomes display intranucleosomal accessibility—termed nucleosome “distortion.”
The study reports domain- and expression-specific patterns of distortion, correlations between transcription factor motifs and distinct distortion types, and experimental evidence that transcription factors directly regulate nucleosome structure. IDLI also captures developmentally encoded distortion patterns during human endoderm differentiation and in primary mouse hepatocytes. Genetic experiments indicate that nucleosome-binding domains of pioneer factors like FOXA2 directly affect nucleosome architecture in vivo.
Overall, the work highlights extensive, regulated nucleosome structural variability at the single-molecule level and provides a platform for modeling transcription factor binding, nucleosome remodeling, and cell-type-specific chromatin regulation across biological contexts.