An integrated view of the structure and function of the human 4D nucleome.
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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,
Andréa Willemin,
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 Park,
Burak H Alver,
Andrew Schroeder,
Rahi Navelkar,
Clara Bakker,
William Ronchetti,
Shannon Ehmsen,
Alexander 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,
Feng Yue
Abstract
The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales. The data reveal a rich complexity of chromatin domains and their sub-nuclear positions, and over one hundred thousand structural loops and promoter-enhancer interactions. We developed 3D models of population-based and individual cell-to-cell variation in genome structure, establishing connections between chromosome folding, nuclear organization, chromatin looping, gene transcription, and DNA replication. We demonstrate the use of computational methods to predict genome folding from DNA sequence, uncovering potential effects of genetic variants on genome structure and function. Together, this comprehensive analysis contributes insights into human genome organization and enhances our understanding of connections between the regulation of genome function and 3D genome organization in general.