For many years, researchers believed that the DNA inside a newly fertilized egg started out as a structural ‘blank slate’ — a loose and disorganized bundle that would only gain order once the embryo began using its own genes. In that traditional view, the genome remained largely unstructured until it “woke up” and initiated its genetic program.
New research published in Nature Genetics challenges that long held assumption. Professor Juanma Vaquerizas and his colleagues report that the genome already shows an unexpected level of organization at this earliest stage. The team developed a new technology called Pico-C that allows scientists to examine the 3D structure of the genome in remarkable detail. With this approach, they found that well before the genome fully activates — a milestone known as Zygotic Genome Activation — an elaborate 3D scaffold of DNA is already taking shape.
This early folding pattern is not just a structural curiosity. The way DNA is arranged in space determines which genes can be switched on during development. That control is essential for proper cell function and helps prevent developmental abnormalities and disease.
“We used to think of the time before the genome awakens as a period of chaos,” explains Noura Maziak, lead author of the study. “But by zooming in closer than ever before, we can see that it’s actually a highly disciplined construction site. The scaffolding of the genome is being erected in a precise, modular way, long before the ‘on’ switch is fully flipped.”
Pico-C Technology Maps DNA Folding in Fruit Flies
The discovery was made using the fruit fly (Drosophila), a model organism widely used in genetics research. During the first few hours after fertilization, a fruit fly embryo rapidly divides its nuclei, producing thousands of cells in a short time. This fast developmental pace makes it an ideal system for studying how genomes are organized and regulated.
Using their highly sensitive Pico-C method, the researchers mapped the 3D arrangement of the fruit fly genome during these early stages. They found that DNA loops and folds according to a modular pattern, enabling different regulatory signals to influence specific regions of the genome. This intricate architecture ensures that genetic information is prepared and positioned for activation exactly when needed.
In addition to delivering detailed views of DNA structure, Pico-C requires only very small samples — about ten times less material than standard techniques. This efficiency makes it possible to investigate how DNA folding shapes gene regulation and how disruptions in this architecture may contribute to disease with far greater precision.
When Genome Architecture Collapses in Human Cells
Although the structural “blueprint” was first identified in fruit flies, its relevance extends to human biology. In a companion study published in Nature Cell Biology led by Professor Ulrike Kutay and collaborators at ETH Zürich in Switzerland, researchers applied the same high resolution mapping strategy to human cells.
They examined what happens when the molecular ‘anchors’ that stabilize the genome’s 3D structure are removed. The findings were striking. When this structural framework falls apart, human cells interpret the breakdown as if they are under viral attack. This misinterpretation activates the cell’s innate immune system, creating a false alarm that can lead to inflammation and disease.
“These two studies tell a complete story,” says Juanma. “The first shows us how the genome’s 3D structure is carefully built at the start of life. The second shows us the disastrous consequences for human health if that structure is allowed to collapse.”
This study was funded by the Medical Research Council and the Academy of Medical Sciences (AMS) through an AMS Professorship award.