A glowing digital representation of a DNA double helix structure.Getty Images
The human genome is no longer just a sequence to be read. It’s a dynamic structure that twists, folds, and reshapes itself in ways that help determine how life functions at the cellular level.
In a major advance for genetic science, researchers at Northwestern University, working with the international 4D Nucleome Project, have produced the most detailed maps yet of how human DNA organizes itself in three dimensions over time.
The work offers an unprecedented look at how genes interact physically inside the nucleus as cells grow, function, and divide.
The study focused on human embryonic stem cells and fibroblasts, two critical cell types for understanding development and cellular behavior.
By tracking how DNA moves and folds, the researchers uncovered how spatial organization plays a central role in regulating gene activity.
“Understanding how the genome folds and reorganizes in three dimensions is essential to understanding how cells function,” said Feng Yue, co-corresponding author of the study.
“These maps give us an unprecedented view of how genome structure helps regulate gene activity in space and time.”
Rather than existing as a linear string of genetic code, DNA forms loops, compartments, and domains inside the nucleus.
These physical structures influence which genes are switched on or off, shaping cell identity, development, and disease progression.
Genome folds into function
To capture this complexity, the research team combined multiple advanced genomic technologies into a single, unified dataset.
No single method can fully describe the genome’s structure, so the study carefully integrated complementary approaches to build a clearer picture.
The effort revealed more than 140,000 chromatin loops per cell type, identifying the molecular elements that anchor these loops and control gene regulation.
It also produced comprehensive classifications of chromosomal domains, showing where they reside within the nucleus.
High-resolution 3D genome models were generated at the single-cell level, allowing scientists to see how individual genes are positioned relative to neighboring genes and regulatory elements.
These maps also exposed how genome architecture varies from one cell to another.
The findings show that changes in DNA folding are closely tied to essential cellular processes such as transcription and DNA replication, helping explain why genetically identical cells can behave very differently.
Predicting disease from structure
Beyond mapping, the researchers also benchmarked the strengths and limitations of different genome-mapping techniques, offering a practical guide for future studies exploring nuclear organization.
Crucially, the team developed computational tools capable of predicting how a genome will fold based solely on its DNA sequence.
This means scientists may one day forecast how genetic variants, especially those linked to disease, alter genome structure without running complex lab experiments.
“Since the majority of variants associated with human diseases are located in the non-coding regions of the genome, it is critical to understand how these variants influence essential gene expression and contribute to disease,” Yue said.
“The 3D genome organization provides a powerful framework for predicting which genes are likely to be affected by these pathogenic variants.”
The approach could accelerate the identification of disease-causing mutations and uncover hidden mechanisms behind inherited disorders, cancers, and developmental conditions.
Looking ahead, the researchers hope their work will enable therapies that target genome architecture itself.
“Having observed 3D genome alterations across cancers, including leukemia and brain tumors, our next aim is to explore how these structures can be precisely targeted and modulated using drugs such as epigenetic inhibitors,” Yue said.
The findings have been published in the journal Nature.
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