The findings, published in Nature by the 4D Nucleome consortium, include contributions from researchers at the Warsaw University of Technology and the University of Warsaw. The work provides the first detailed atlas of how DNA is arranged in three-dimensional space and how that structure changes dynamically.

Every human cell contains roughly two metres of DNA compressed into a nucleus only a few micrometres in diameter. For decades, scientists have known that this packing is not random. Genes and regulatory elements must be positioned so they can interact precisely, turning biological processes on and off at the right time. What has been less clear is how this spatial organisation changes—and how those changes affect function.

The 4D Nucleome project set out to answer that question by mapping not only where DNA sits in three-dimensional space, but how its configuration evolves over time—the fourth dimension.

‘You could say that the 4D Nucleome project is a natural continuation of earlier research on the human genome. In the early 2000s, as part of the Human Genome Project, an international team of scientists deciphered the complete genome sequence of one person. Then, the 1000 Genomes project allowed us to understand the DNA sequences of many individuals, revealing enormous inter-human variability - from single nucleotide mutations to larger structural variants such as deletions and duplications. The next step was the identification and interpretation of epigenomic patterns (e.g., DNA methylation and other post-translational modifications of DNA-interacting proteins) in numerous cell lines representing the main human tissues. And finally, we have now focused on the spatial arrangement of chromatin (DNA with its associated proteins) in the nucleus, and on its dynamics over time, which will allow us to better understand how genome structure affects cell function’, Professor Dariusz Plewczyński says.

At the heart of the discovery is chromatin: DNA wrapped around proteins, forming a complex structure that folds into loops and domains. Advanced imaging and 3D genomics techniques reveal that distant parts of the genome—separated by millions of base pairs along the linear sequence—can be brought into close proximity in physical space.

These contacts are not accidental. They reflect functional relationships, particularly between gene promoters and regulatory elements known as enhancers. Enhancers act as switches, activating genes in specific tissues or under specific conditions.

‘The proximity of regulatory elements to a given gene's promoter in 3D space affects the level of expression of that gene, i.e., its activity in a given cell and at a given time. We have demonstrated that the relationship between the spatial proximity of DNA fragments and their biological function influences genome activity’, Plewczyński says.

This spatial logic helps explain how identical DNA sequences can produce vastly different cell types. A neuron and a liver cell contain the same genome, but their chromatin is organised differently, allowing different sets of genes to be activated.

Importantly, there is no single “correct” 3D structure. Each cell type—and even each individual cell—can exhibit a range of possible configurations, forming a dynamic ensemble rather than a fixed architecture.

What distinguishes the new atlas is its focus on change. DNA inside the nucleus is not static; it is constantly reorganising in response to internal and external signals.

Researchers tracked these dynamics across different stages of the cell cycle and under varying environmental conditions. This revealed how chromatin rearranges to support processes such as cell division, stress responses or adaptation to limited oxygen.

‘We did not stop at a single +frozen+ image of the genome. In a living organism, DNA is constantly moving and reorganizing. Understanding this dynamics has significant practical implications’, Plewczyński says.

This temporal dimension helps explain how cells rapidly adjust gene activity. When needed, specific genes can be repositioned within the nucleus to interact more effectively with their regulatory partners, while others are silenced.

One of the most significant implications of the research concerns genetic mutations. Traditionally, scientists have focused on changes that alter protein-coding sequences. But the 4D nucleome shows that mutations can also have structural effects.

Changes in non-coding regions—long considered “junk DNA”—may shift the position of genes in three-dimensional space. This can disrupt their contact with enhancers or other regulatory elements, altering gene expression without changing the protein itself.

Such mechanisms may underlie diseases that cannot be explained by sequence changes alone, offering a new framework for interpreting genetic variation.

The analogy, researchers suggest, is similar to protein science: just as the sequence of amino acids determines a protein’s 3D structure and function, the genome’s sequence influences its spatial folding—though on a far more complex scale, involving billions of base pairs.

Beyond mapping, the project also integrates computational modelling and artificial intelligence to predict how genome structure changes under different conditions. The Polish team contributed models that simulate chromatin dynamics and forecast how mutations—such as deletions or point changes—might reshape the genome’s 3D architecture and affect gene activity.

This predictive capability could prove crucial for biomedical research, helping scientists anticipate the functional consequences of genetic variants and identify targets for therapy.

The broader aim is to link three layers of biological information: gene expression, epigenetic modifications and spatial genome organisation. Together, these data can provide clues about the roles of previously uncharacterised DNA regions and the processes they influence.

While this does not yet deliver a complete understanding of gene function, it allows researchers to generate informed hypotheses about how specific regions of the genome behave in different tissues and at different times.

The 4D Nucleome project brought together hundreds of scientists from dozens of institutions worldwide, spanning genetics, cell biology, bioinformatics, biophysics and mathematics. It reflects the increasing scale and interdisciplinarity of modern biology, where experimental data and computational analysis are tightly intertwined.

By moving beyond the static genome to a dynamic, four-dimensional view, the research opens a new chapter in understanding how life’s blueprint operates in real time—and how its disruption can lead to disease.

Katarzyna Czechowicz (PAP)

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