The 3D genome

The 3D configurations of the genome and the nucleus are complex, dynamic and crucial for the proper control of gene expression and physiology. In the past few years, technological advances in the investigation of higher-order chromatin structure and function — pioneered by chromosome conformation capture methods and by improved microscopy techniques — revealed how the organization of the genome is interconnected with nuclear architecture and can vary between cell types and during cell differentiation and development. Not surprisingly, mutations that alter nuclear architecture cause many human conditions and diseases, which have shed light on the molecular mechanisms that underlie the connections between nuclear organization and physiology.

This collection includes recent Reviews, Research articles and Protocols from across the Nature group of journals — it showcases both the latest advances in the methodologies used to study genome organization and our emerging understanding of how genome organization and nuclear architecture regulate gene expression, cell fate and cell function in physiology and disease.

The content of this collection has been chosen by the editors of Nature Reviews Molecular Cell Biology.


  • Nature Reviews Molecular Cell Biology | Review

    The three-dimensional (3D) organization of eukaryote chromosomes regulates genome function and nuclear processes such as DNA replication, transcription and DNA-damage repair. Experimental and computational methodologies for 3D genome analysis have been rapidly expanding, with a focus on high-throughput chromatin conformation capture techniques and on data analysis.

    • Anthony D. Schmitt
    • , Ming Hu
    •  &  Bing Ren
  • Nature Reviews Molecular Cell Biology | Review

    Mechanistic insights are emerging into how long non-coding RNAs (lncRNAs) regulate gene expression by coordinating regulatory proteins, localizing to genomic loci and shaping nuclear organization. Interestingly, lncRNAs can perform functions that cannot be carried out by DNA elements or proteins alone, such as amplifying regulatory signals in the nucleus.

    • Jesse M. Engreitz
    • , Noah Ollikainen
    •  &  Mitchell Guttman
  • Nature Reviews Molecular Cell Biology | Review

    Mutations in non-coding parts of the genome can cause disease. Technological advances are providing unprecedented detail on genome organization and folding, and have revealed that enhancer–target gene coupling is spatially restricted, as it occurs within topologically associated domains (TADs), and that disrupting such organization can lead to disease-associated gene dysregulation.

    • Peter Hugo Lodewijk Krijger
    •  &  Wouter de Laat
  • Nature Reviews Molecular Cell Biology | Comment

    Job Dekker asserts that cases in which data from microscopy- and 3C-based methods appear discordant about genome organization will provide opportunities to improve our models of chromatin folding.

    • Job Dekker
  • Nature Reviews Molecular Cell Biology | Review

    Genome-wide mapping of chromatin contacts reveals the structural and organizational changes that the metazoan genome undergoes during cell differentiation. These changes involve entire chromosomes, which are influenced by contacts with nuclear structures such as the lamina, and local interactions mediated by transcription factors and chromatin looping.

    • Ana Pombo
    •  &  Niall Dillon
  • Nature Reviews Genetics | Review

    In this article the authors review current knowledge on chromatin architecture and the molecular mechanisms that underlie it. They discuss how three-dimensional (3D) organization of chromatin relates to gene expression, development and disease, and consider its effect on genome evolution.

    • Boyan Bonev
    •  &  Giacomo Cavalli

Research and Protocols

  • Nature | Letter

    High-resolution three-dimensional maps of chromatin contacts in the developing human brain help to identify enhancer–promoter contacts, many of which are associated with human cognitive function and disease.

    • Hyejung Won
    • , Luis de la Torre-Ubieta
    • , Jason L. Stein
    • , Neelroop N. Parikshak
    • , Jerry Huang
    • , Carli K. Opland
    • , Michael J. Gandal
    • , Gavin J. Sutton
    • , Farhad Hormozdiari
    • , Daning Lu
    • , Changhoon Lee
    • , Eleazar Eskin
    • , Irina Voineagu
    • , Jason Ernst
    •  &  Daniel H. Geschwind
  • Nature | Letter

    Genomic duplications in the SOX9 region are associated with human disease phenotypes; a study using human cells and mouse models reveals that the duplications can cause the formation of new higher-order chromatin structures called topologically associated domains (TADs) thereby resulting in changes in gene expression.

    • Martin Franke
    • , Daniel M. Ibrahim
    • , Guillaume Andrey
    • , Wibke Schwarzer
    • , Verena Heinrich
    • , Robert Schöpflin
    • , Katerina Kraft
    • , Rieke Kempfer
    • , Ivana Jerković
    • , Wing-Lee Chan
    • , Malte Spielmann
    • , Bernd Timmermann
    • , Lars Wittler
    • , Ingo Kurth
    • , Paola Cambiaso
    • , Orsetta Zuffardi
    • , Gunnar Houge
    • , Lindsay Lambie
    • , Francesco Brancati
    • , Ana Pombo
    • , Martin Vingron
    • , Francois Spitz
    •  &  Stefan Mundlos
  • Nature | Letter

    An in-depth analysis of the structure, chromatin accessibility and expression status of the mouse inactive X (Xi) chromosome provides insights into the regulation of Xi chromosome structure, its dependence on the macrosatellite DXZ4 region, the Xist non-coding RNA, as well as the basis for topologically associating domain (TAD) formation on the Xi.

    • Luca Giorgetti
    • , Bryan R. Lajoie
    • , Ava C. Carter
    • , Mikael Attia
    • , Ye Zhan
    • , Jin Xu
    • , Chong Jian Chen
    • , Noam Kaplan
    • , Howard Y. Chang
    • , Edith Heard
    •  &  Job Dekker
  • Nature | Letter

    Using super-resolution imaging to directly observe the three-dimensional organization of Drosophila chromatin at a scale spanning sizes from individual genes to entire gene regulatory domains, the authors find that transcriptionally active, inactive and Polycomb-repressed chromatin states each have a distinct spatial organisation.

    • Alistair N. Boettiger
    • , Bogdan Bintu
    • , Jeffrey R. Moffitt
    • , Siyuan Wang
    • , Brian J. Beliveau
    • , Geoffrey Fudenberg
    • , Maxim Imakaev
    • , Leonid A. Mirny
    • , Chao-ting Wu
    •  &  Xiaowei Zhuang
  • Nature | Letter

    An epigenetic mechanism in which gain-of-function IDH mutations promote gliomagenesis by disrupting chromosomal topology is presented, with IDH mutations causing the binding sites of the methylation-sensitive insulator CTCF to become hypermethylated; disruption of a CTCF boundary near the glioma oncogene PDGFRA allows a constitutive enhancer to contact and activate the oncogene aberrantly.

    • William A. Flavahan
    • , Yotam Drier
    • , Brian B. Liau
    • , Shawn M. Gillespie
    • , Andrew S. Venteicher
    • , Anat O. Stemmer-Rachamimov
    • , Mario L. Suvà
    •  &  Bradley E. Bernstein
  • Nature | Letter

    Genome-wide chromosome conformation capture analysis in C. elegans reveals that the dosage compensation complex, a condensin complex, remodels the X chromosomes of hermaphrodites into a sex-specific topology distinct from autosomes while regulating gene expression chromosome-wide.

    • Emily Crane
    • , Qian Bian
    • , Rachel Patton McCord
    • , Bryan R. Lajoie
    • , Bayly S. Wheeler
    • , Edward J. Ralston
    • , Satoru Uzawa
    • , Job Dekker
    •  &  Barbara J. Meyer