For a few years, researchers believed that the DNA inside a newly fertilized egg began as a structural ‘blank slate' – a loose and disorganized bundle that might only come into order when the embryo began using its genes. In this traditional view, the genome remained largely unstructured until it “woke up” and initiated its genetic program.
New research published in challenges long-held assumptions. Professor Juanma Vaquerizas and colleagues report that the genome already shows unexpected levels of organization at this early stage. The team has developed a brand new technology called Pico-C that permits scientists to look at the 3D structure of the genome in remarkable detail. With this approach, they found that even before the genome is fully activated — a milestone generally known as Zygotic Genome Activation — an elaborate 3D scaffold of DNA is already forming.
This early folding pattern shouldn't be only a structural curiosity. The way DNA is arranged in space determines which genes may be turned on during development. This control is important for correct cell function and helps prevent developmental abnormalities and disease.
“We used to think of the time before the awakening of the genome as a period of chaos,” explains Nora Maziak, lead creator of the study. “But zooming in closer than ever, we can see that this is actually a very disciplined construction site. The scaffolding of the genome is being erected in precise, modular fashion 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 utilized in genetics research. During the primary few hours after fertilization, a fruit fly embryo rapidly divides its nucleus, producing 1000's of cells in a brief time period. This rapid growth rate makes it a super system for studying how genomes are organized and controlled.
Using their highly sensitive Pico-C method, the researchers mapped the 3D sequence of the fruit fly genome during these early stages. They found that DNA loops and folds in line with a modular pattern, enabling different regulatory signals to affect specific regions of the genome. This complex architecture ensures that genetic information is prepared and positioned for activation when needed.
In addition to providing detailed views of DNA structure, pico-C requires only very small samples — about ten times less material than standard techniques. This performance makes it possible to research how DNA folding shapes gene regulation and the way disruptions on this architecture may contribute to disease with greater precision.
When genome architecture breaks down in human cells.
Although the structural “blueprint” was first identified in fruit flies, its relevance extends to human biology. In a companion study led by Professor Ulrike Kutay and colleagues at ETH Zürich in Switzerland, researchers applied the identical high-resolution mapping technique to human cells.
They examined what happens when the molecular ‘anchors' that stabilize the 3D structure of the genome are removed. The results were surprising. When this structural framework breaks down, human cells interpret the disorder as in the event that they are under viral attack. This misinterpretation triggers the cell's innate immune system, making a false alarm that may result in inflammation and disease.
“These two studies tell a complete story,” says Juanma. “The first shows us how the 3D structure of the genome is carefully constructed at the beginning of life. The second shows us that if this structure is allowed to collapse, there will be catastrophic consequences for human health.”
This study was funded by the Medical Research Council and the Academy of Medical Sciences (AMS) through an AMS Professorship Award.