An integrated view of the structure and function of the human 4D nucleome

The dynamic three-dimensional (3D) organization of the human genome (the 4D nucleome) is linked to genome function. Here we describe efforts by the 4D Nucleome Project<sup>1</sup> to map and analyse the 4D nucleome in widely used H1 human embryonic stem cells and immortalized fibroblasts (HFFc6). We produced and integrated diverse genomic datasets of the 4D nucleome, each contributing unique observations, which enabled us to assemble extensive catalogues of more than 140,000 looping interactions per cell type, to generate detailed classifications and annotations of chromosomal domain types and their subnuclear positions, and to obtain single-cell 3D models of the nuclear environment of all genes including their long-range interactions with distal elements. Through extensive benchmarking, we describe the unique strengths of different genomic assays for studying the 4D nucleome, providing guidelines for future studies. Three-dimensional models of population-based and individual cell-to-cell variation in genome structure showed connections between chromosome folding, nuclear organization, chromatin looping, gene transcription and DNA replication. Finally, we demonstrate the use of computational methods to predict genome folding from DNA sequence, which will facilitate the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.

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Publication Details

Journal
Nature
Published
2025-12-17
DOI
https://doi.org/10.1038/s41586-025-09890-3
Citations
11
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
8.87
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article

An integrated view of the structure and function of the human 4D nucleome

Derek H. Janssens, Ruochi Zhang, Ming Hu, Katherine S. Pollard et al.
11 citations
Nature
Genomics and Chromatin Dynamics
8.87
article

An integrated view of the structure and function of the human 4D nucleome

Derek H. Janssens, Ruochi Zhang, Ming Hu, Katherine S. Pollard, Shuzhen Kuang, Ping Wang, Nils Krietenstein, William Ronchetti, Xingzhao Wen, Kaustav Sengupta, Lorenzo Boninsegna, Steven Henikoff, Rieke Kempfer, David M. Gilbert, Daniel J. Emerson, Mateusz Chiliński, Dariusz Plewczyński, Peter J. Park, Sergey V. Venev, Miriam K. Minsk, Simona Bianco, Daan Peric‐Hupkes, Pradeep Kumar, Sofia A. Quinodoz, Liyan Yang, Job Dekker, Mario Nicodemi, Frank Alber, Aslı Yıldırım, Oliver J. Rando, Tom van Schaik, Mattia Conte, Feng Yue, Sheng Zhong, W. R. Zhao, Shannon Ehmsen, Alexander Kukalev, Takayo Sasaki, Mitchell Guttman, Laura Brueckner, Dominik Szabó, Betul Akgol Oksuz, William Stafford Noble, Alex Abraham, Andrea M. Chiariello, Bas van Steensel, Qiuyang Wu, Christoph J. Thieme, Warren Winick‐Ng, Nils Gehlenborg, Shu Chien, Claire Marchal, Ana Pombo, Jennifer E. Phillips‐Cremins, Alexander Veit, Bing Ren, Andréa Willemin, Ashley L. Cook, Johan H. Gibcus, Daofeng Li, Prashant Bhat, Andrew J. Schroeder, Teresa Szczepińska, B. Alver, Clara Bakker, Andrew S. Belmont, Andrea Esposito, Minji Kim, Yang Zhang, Yun Li, Yuan Liu, Yang Yang, Ye Wang, Ting Wang, Ran Zhang, Jie Liu, Jian Ma, Xiaotao Wang, Liguo Zhang, Yuxiang Zhan, Jie Xu, Lindsay Lee, Peiyao Zhao, Yuchuan Wang, Miao Yu, Rahi Navelkar, Ibai Irastorza Azcarate, Y Ruan, R. Jordan Barnett, Haoxi Chai
article en
11 citations

Abstract

The dynamic three-dimensional (3D) organization of the human genome (the 4D nucleome) is linked to genome function. Here we describe efforts by the 4D Nucleome Project<sup>1</sup> to map and analyse the 4D nucleome in widely used H1 human embryonic stem cells and immortalized fibroblasts (HFFc6). We produced and integrated diverse genomic datasets of the 4D nucleome, each contributing unique observations, which enabled us to assemble extensive catalogues of more than 140,000 looping interactions per cell type, to generate detailed classifications and annotations of chromosomal domain types and their subnuclear positions, and to obtain single-cell 3D models of the nuclear environment of all genes including their long-range interactions with distal elements. Through extensive benchmarking, we describe the unique strengths of different genomic assays for studying the 4D nucleome, providing guidelines for future studies. Three-dimensional models of population-based and individual cell-to-cell variation in genome structure showed connections between chromosome folding, nuclear organization, chromatin looping, gene transcription and DNA replication. Finally, we demonstrate the use of computational methods to predict genome folding from DNA sequence, which will facilitate the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.

NatureVol. 649(8097)
QB3 (US), Warsaw University of Technology (PL), Northwestern University (US), University of North Carolina at Chapel Hill (US), California Institute of Technology (US), University of Copenhagen (DK), Cleveland Clinic (US), Van Andel Institute (US), Gladstone Institutes (US), Howard Hughes Medical Institute (US), Harvard University (US), University of Illinois Urbana-Champaign (US), University of California, Los Angeles (US), University of Massachusetts Chan Medical School (US), Princeton University (US), University of Washington (US), Washington University in St. Louis (US), Max Delbrück Center (DE), Fudan University (CN), University of Michigan (US), Novo Nordisk Foundation (DK), The Netherlands Cancer Institute (NL), University of California San Diego (US), Fred Hutch Cancer Center (US), Oncode Institute (NL), Federico II University Hospital (IT), San Diego Biomedical Research Institute (US), Institute of Human Genetics (PL), La Jolla Bioengineering Institute (US), Obstetrics and Gynecology Hospital of Fudan University (CN), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, University of Warsaw (PL), University of Naples Federico II (IT), Carnegie Mellon University (US), Zhejiang University (CN), Newbury College (US), Philadelphia University (US)
Openalex Percentile: Top 2%
Genomics and Chromatin Dynamics
8.87
DOIOpen Access PDFOpenAlex
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