Scientists have created the most detailed maps yet of how the human genome folds and reorganizes inside cells, revealing a hidden layer of genetic regulation that unfolds across space and time. Credit: Shutterstock

The research represents a major step forward in revealing how the three dimensional form of DNA shapes the way human biology functions.

In a major step toward understanding how the physical form of DNA shapes human biology, researchers at Northwestern University working with the 4D Nucleome Project have created the most comprehensive maps yet of the genome’s three-dimensional organization over time and space. The work is described in a new study published in Nature.

The research, based on experiments in human embryonic stem cells and fibroblasts, provides an expansive picture of how genes interact with one another, fold into complex structures, and shift their positions as cells carry out normal functions and divide. The study was co-led by Feng Yue, the Duane and Susan Burnham Professor of Molecular Medicine in the Department of Biochemistry and Molecular Genetics.

“Understanding how the genome folds and reorganizes in three dimensions is essential to understanding how cells function,” said Yue, who is also director of the Center for Advanced Molecular Analysis and founding director of the Center for Cancer Genomics at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “These maps give us an unprecedented view of how genome structure helps regulate gene activity in space and time.”

Inside the cell nucleus, DNA does not remain stretched out in a simple, linear form. Instead, it folds into loops and distinct regions that bring distant sections of the genome into close contact. These physical arrangements help control which genes are active or silent, shaping processes such as development, cell identity, and disease.

Building a Unified 4D Genome Dataset

To study this complexity, Yue and his international collaborators employed a wide array of genomic technologies on fibroblasts and human embryonic stem cells to produce a unified dataset.

This effort identified:

• More than 140,000 chromatin loops per cell type, identifying the underlying elements at the different types of loop anchors and how they contribute to gene regulation.
• Comprehensive classifications of chromosomal domains, including where they reside inside the nucleus.
• High‑resolution 3D models of entire genomes at the single‑cell level, showing how each gene is positioned relative to its neighbors and regulatory elements.

These maps reveal how the genome’s architecture varies from cell to cell and how these variations relate to essential processes, including transcription and DNA replication.

Evaluating Technologies and Predicting Genome Folding

Because no single technology can fully capture the genome’s 4D structure, the study also assessed the capabilities and limitations of the methods involved. Through extensive benchmarking, the investigators identified which assays are best suited to detect loops, domain boundaries, or nuanced differences in nuclear positioning — providing a roadmap for scientists pursuing similar questions in the future.

Additionally, by developing computational tools capable of predicting how the genome will fold purely from its sequence, the study authors have set the stage for future scientists to estimate how genetic variants — including those linked to disease — might alter 3D genome architecture, all without needing to run complex experiments.

This advance could accelerate the discovery of pathogenic mutations and reveal previously hidden mechanisms behind inherited disorders, Yue said.

“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 a More Complete View of the Genome

The work underscores a growing recognition that the genome’s function cannot be understood only by reading its sequence and that its shape matters, too. By revealing the connections between DNA folding, chromatin loops, gene activity, and cell behavior, the study moves the field closer to a holistic view of how genetic instructions operate inside living cells.

Moving forward, Yue said he hopes these tools will eventually help decode how genome misfolding contributes to cancers, developmental disorders, and other conditions, opening the door to structural genomics-based diagnostics and therapies.

“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.&

Reference: “An integrated view of the structure and function of the human 4D nucleome” by Job Dekker, Betul Akgol Oksuz, Yang Zhang, Ye Wang, Miriam K. Minsk, Shuzhen Kuang, Liyan Yang, Johan H. Gibcus, Nils Krietenstein, Oliver J. Rando, Jie Xu, Derek H. Janssens, Steven Henikoff, Alexander Kukalev, Willemin Andréa, Warren Winick-Ng, Rieke Kempfer, Ana Pombo, Miao Yu, Pradeep Kumar, Liguo Zhang, Andrew S. Belmont, Takayo Sasaki, Tom van Schaik, Laura Brueckner, Daan Peric-Hupkes, Bas van Steensel, Ping Wang, Haoxi Chai, Minji Kim, Yijun Ruan, Ran Zhang, Sofia A. Quinodoz, Prashant Bhat, Mitchell Guttman, Wenxin Zhao, Shu Chien, Yuan Liu, Sergey V. Venev, Dariusz Plewczynski, Ibai Irastorza Azcarate, Dominik Szabó, Christoph J. Thieme, Teresa Szczepińska, Mateusz Chiliński, Kaustav Sengupta, Mattia Conte, Andrea Esposito, Alex Abraham, Ruochi Zhang, Yuchuan Wang, Xingzhao Wen, Qiuyang Wu, Yang Yang, Jie Liu, Lorenzo Boninsegna, Asli Yildirim, Yuxiang Zhan, Andrea Maria Chiariello, Simona Bianco, Lindsay Lee, Ming Hu, Yun Li, R. Jordan Barnett, Ashley L. Cook, Daniel J. Emerson, Claire Marchal, Peiyao Zhao, Peter J. Park, Burak H. Alver, Andrew J. Schroeder, Rahi Navelkar, Clara Bakker, William Ronchetti, Shannon Ehmsen, Alexander D. Veit, Nils Gehlenborg, Ting Wang, Daofeng Li, Xiaotao Wang, Mario Nicodemi, Bing Ren, Sheng Zhong, Jennifer E. Phillips-Cremins, David M. Gilbert, Katherine S. Pollard, Frank Alber, Jian Ma, William S. Noble and Feng Yue, 17 December 2025, Nature. DOI: 10.1038/s41586-025-09890-3

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