It is hard to imagine how two meters of DNA can be squeezed into a tiny cell nucleus – analogous to packing a fishing line stretching across the length of Switzerland into an Emmentaler cheese wheel. And all this without becoming hopelessly tangled. Yet almost every cell in our body accomplishes this remarkable feat of packaging. But DNA cannot simply be crammed into the nucleus. Genes must remain accessible when needed, and the genetic material must be copied and repaired.
"We know that chromosomes are not randomly arranged within the nucleus," explains Prof. Susan Mango. "But for a long time, there was a gap between what we could see under the microscope and what molecular studies told us about how DNA is organized."
While microscopy revealed distinct structures resembling small neighborhoods, molecular studies identified two major organizational principles: topologically associating domains (TADs), in which neighboring stretches of DNA frequently interact, and larger compartments in which TADs are grouped together.
Hidden structures revealed
The researchers investigated how chromosomes are organized during early embryonic development in the roundworm C. elegans. The key was looking at individual DNA molecules one by one. Previous studies had suggested that, unlike in vertebrates, TADs were largely absent from C. elegans. However, these studies relied on measurements averaged across thousands of DNA molecules, potentially obscuring individual structures.
First author Dania Camila Pulido-Barrera therefore took a different approach. Using a microscopy-based technique called chromatin tracing, she examined individual DNA molecules and grouped them according to their three-dimensional folding patterns.
"When you average thousands of DNA molecules together, important differences can disappear," explains Pulido-Barrera. "By looking at individual molecules, we were able to discover structures that had previously remained hidden."
Three types of chromosomal domains discovered
The researchers identified three distinct types of large chromosomal domains within heterochromatin, the densely packed regions of the genome. These domains differ not only in their three-dimensional structure but also in the mechanisms through which they form. One type closely resembles the TADs found in vertebrates. Another houses a set of genes critical to make ribosomes, the factories that produce proteins in cells. This domain, called the 5S eICID, is distinct from the well-known nucleolus and also behaves differently from TADs.
"The big surprise was the diversity," says Pulido-Barrera. "We discovered different ways in which these large regions of DNA can be organized within the cell nucleus."
The findings, published in the scientific journal Nature Structural & Molecular Biology, challenge the previous assumption that C. elegans lacks large, clearly defined TAD-like domains on its autosomes. They also suggest that fundamental principles of chromosome organization are more widespread across the animal kingdom than previously thought.
From structure to function
The next step is to investigate what functions these structures serve. "We now know that these different domains exist. But the big question is what function they serve," explains Mango. "What happens when we disrupt them? And how does this affect gene regulation?"
The research team will also use the model organism C. elegans for these investigations. Pulido-Barrera’s study has once again shown that it is well suited to addressing such questions.
Original publication:
Dania Camila Pulido-Barrera, Jia E. You, Angelo L. Angonezi, Alexander Kuznetsov, Fei Xu, Tobias Verheijen, Ahilya N. Saw, Pavel Kos, Luca Giorgetti, Nacho Molina, David Brückner and Susan E. Mango. Single-molecule chromatin tracing reveals a diversity of megabase heterochromatin domains. Nature Structural & Molecular Biology, published online 2 October 2026
Contact: Communications, Heike Sacher