A hidden world inside DNA is finally revealed

• Offers a sweeping new look at how genes interact, fold, and shift position as cells grow, function, and divide
• May speed the discovery of disease causing genetic mutations and uncover hidden mechanisms behind inherited disorders
• Researchers hope the tools will eventually reveal how errors in genome folding contribute to cancer, developmental disorders, and other diseases

In a major step toward understanding how DNA structure shapes human biology, scientists at Northwestern University working with the 4D Nucleome Project have produced the most detailed maps yet of how the human genome is organized in three dimensions and how that organization changes over time. The research, published in Nature, provides a new window into how DNA operates inside living cells.

The team created these maps using human embryonic stem cells and fibroblasts. Together, the data offer a broad look at how genes interact, fold, and shift positions as cells carry out their normal functions and divide, said co-corresponding author Feng Yue, the Duane and Susan Burnham Professor of Molecular Medicine in the department of biochemistry and molecular genetics at Northwestern.

"Understanding how the genome folds and reorganizes in three dimensions is essential to understanding how cells function," Yue said. "These maps give us an unprecedented view of how genome structure helps regulate gene activity in space and time."

DNA Structure Shapes Gene Activity

DNA inside the cell does not exist as a straight, linear strand. Instead, it bends into loops and forms distinct compartments within the cell nucleus. These physical arrangements help control which genes are switched on or off, influencing development, cell identity, and the risk of disease.

To capture this complexity, Yue and collaborators from around the world combined multiple advanced genomic techniques. By applying these tools to both fibroblasts and human embryonic stem cells, the researchers assembled a unified and highly detailed dataset that captures genome organization from multiple angles.

What the New Genome Maps Reveal

The analysis uncovered several major features of genome architecture:

• More than 140,000 chromatin loops in each cell type, along with the specific elements that anchor those loops and their role in regulating genes
• Detailed classifications of chromosomal domains and their positions within the nucleus
• High-resolution 3D models of entire genomes at the single-cell level, showing how individual genes are arranged relative to nearby genes and regulatory regions

Together, these findings show that genome structure can vary from one cell to another. The differences are closely tied to essential cellular activities such as transcription and DNA replication.

Evaluating Tools for Studying the 4D Genome

Because no single experimental method can fully capture the genome's four-dimensional organization, the researchers also compared the strengths and limitations of the technologies used. Through extensive benchmarking, they identified which approaches work best for detecting loops, defining domain boundaries, or spotting subtle changes in how DNA is positioned inside the nucleus -- information that can guide future studies in the field.

The team also developed computational tools that can predict how a genome will fold based only on its DNA sequence. These tools make it possible to estimate how genetic variants -- including those linked to disease -- might change 3D genome structure without running complex laboratory experiments.

Implications for Disease and Genetic Risk

Yue said this capability could speed the identification of disease-causing mutations and uncover biological mechanisms behind inherited disorders that were previously difficult to detect.

"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," Yue said.

Toward New Diagnostics and Treatments

The study reinforces a growing view in genetics that reading DNA sequences alone is not enough. The physical shape of the genome also plays a central role. By linking DNA folding, chromatin loops, gene regulation, and cell behavior, the research brings scientists closer to a more complete understanding of how genetic instructions work inside living cells.

Looking ahead, Yue said he hopes these tools will help researchers uncover how errors in genome folding contribute to cancer, developmental disorders, and other diseases, potentially leading to new diagnostic strategies and therapies based on genome structure.

"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.