What the New Study Found
Every human cell packs more than six feet of DNA into a space invisible to the naked eye. Think of it as compressing an entire house into a single sugar cube. To fit inside a cell and stay organized, DNA wraps tightly around protein clusters called nucleosomes.
For decades, scientists believed that DNA wound around a nucleosome stayed locked away. Only unwrapped DNA, the thinking went, could remain active. Now, a landmark study from Gladstone Institutes and the Arc Institute overturns that long-held view entirely.
Using a new AI-powered computational tool, researchers discovered that most nucleosomes hold sections of DNA that are partially accessible to the cell. These sections are not fully packed away. Instead, they exist in a middle state—partly open, partly closed. The team published their findings in the journal Nature on April 29, 2026.
“The conception before was that genes were either turned on or off when it came to nucleosomes,” says Gladstone Investigator Vijay Ramani, PhD. “But we’re finding it’s more like a volume dial. This is a completely new organizational code for the genome.”
How IDLI Works
From SAMOSA to IDLI: Building a Better Tool
The Ramani lab previously developed a technology called SAMOSA, which mapped where nucleosomes sit along individual DNA molecules. Their newer tool, IDLI (Iteratively Defined Lengths of Inaccessibility), builds directly on that foundation.
IDLI uses an AI model trained to spot subtle differences between nucleosome structures inside SAMOSA sequencing data. Rather than simply locating each nucleosome, IDLI scans data in two dimensions—across the DNA fiber and within each nucleosome itself. This dual-axis approach lets researchers probe internal nucleosome structure with far greater precision than before.
Each nucleosome consists of eight distinct building blocks. IDLI can detect whether all eight blocks are present and tightly bound. Missing or loose blocks signal distortion, which means sections of DNA are partially exposed to the cell.
Beyond On and Off: A Dynamic View of Chromatin
The Genome Is More Open Than Scientists Thought
All cells in the body carry identical DNA. Yet different cells use only the genes relevant to their specific roles. To manage this, cells rely on elaborate systems to control which genes stay accessible and which ones remain stored away. Nucleosomes form a key part of this filing system, and scientists study chromatin—all of a cell’s DNA packaged using nucleosomes—to understand which genes a cell actively uses.
When the research team analyzed chromatin from mouse embryonic stem cells, the results proved surprising. More than 85 percent of nucleosomes showed some degree of distortion. Moreover, these distortions were not random. The cell carefully programs each one.
“Our findings suggest the genome is far more dynamic and accessible than the scientific community realized,” Ramani says.
What 14 Nucleosome States Reveal
A New Grammar for Gene Control
The researchers identified 14 distinct structural states of nucleosomes. Each state links to a different level of gene activity. Furthermore, the same patterns appeared in human stem cells developing into liver-like cells, and in liver cells taken directly from mice. This consistency across species and cell types strengthens the discovery’s significance considerably.
Scientists already knew that transcription factors—special proteins that switch genes on and off—play a major role in gene regulation. Now, however, this study shows these proteins also shape nucleosome structures directly. When researchers removed two of these proteins from cells, the nucleosome distortion patterns shifted in predictable ways. Consequently, transcription factors appear to force nucleosomes either to stay open or remain locked shut.
“Before this, our understanding of chromatin was like reading a text that only had sound and silence—just two states of being,” says Hani Goodarzi, PhD, of the Arc Institute. “Now we can see it’s far more nuanced. There are letters and words, and we uncovered a new kind of grammar that controls them.”
Implications for Cancer and Aging Research
Small Gene Shifts Drive Complex Disease
For many complex conditions, scientists have struggled to pinpoint the specific DNA changes that trigger disease. That challenge likely exists because diseases like cancer and neurodegeneration arise from small shifts across many genes at once. A gene that should stay completely off instead gets read by the cell—or vice versa.
Ramani views the 14 nucleosome states as a precise readout for exactly those shifts. “Most complex diseases revolve around gradation,” he explains. “Maybe a gene is on but at half the level it would normally be, or maybe it’s active in the wrong cell type altogether.”
Additionally, the team sees strong promise in aging research. Chromatin structure changes in predictable ways as cells grow older, and some of those changes appear reversible. Therefore, the researchers plan to use IDLI to map how nucleosome states shift across different tissues during aging—work that could eventually point toward therapies restoring healthy chromatin patterns.
What Comes Next for Scientists
Toward Therapies That Restore Healthy Patterns
These findings open a new chapter in genomics. By revealing how nucleosome structure governs gene activity, the study gives researchers a richer toolkit for understanding complex disease. In the future, targeted therapies might restore healthy nucleosome patterns in aging or diseased cells by addressing these newly identified structural states directly.
“These are precisely the states that end up being quite important in terms of disease relevance,” Ramani says.
Ultimately, both researchers aim to move beyond observation. “We’re reading the language,” Goodarzi says, “but we want to learn how to speak it so that we can control and modify it. We’re not here just to observe biology—at some point we want to intervene.”
