An integrated view of the structure and function of the human 4D nucleome.
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,
Feng Yue
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 Project1 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.