Collection |

The 3D genome

The three-dimensional configuration of the genome is complex, dynamic and crucial for gene regulation. In the past few years, technological advances in chromosome conformation capture methods and in 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. This collection includes recent articles from across the Nature group of journals and showcases both the latest advances in the methodologies used to study genome organization, and our recent 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.

Reviews

For appropriate control of gene expression, enhancers must communicate with the right target genes at the right time, typically over large genomic distances. In this Review, Schoenfelder and Fraser discuss our latest understanding of long-range enhancer–promoter crosstalk, including target-gene specificity, interaction dynamics, protein and RNA architects of interactions, roles of 3D genome organization and the pathological consequences of regulatory rewiring.

Review Article | | Nature Reviews Genetics

Mechanical cues from the microenvironment can be efficiently transmitted to the nucleus to engage in the regulation of genome organization and gene expression. Recent technological and theoretical progress sheds new light on the relationships between cell mechanics, nuclear and chromosomal architecture and gene transcription.

Review Article | | Nature Reviews Molecular Cell Biology

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.

Review Article | | Nature Reviews Molecular Cell Biology

Recent studies show that structural variation can alter the genome architecture, leading to changes in the regulation of gene expression that cause disease. The authors review the role of genetic structural variation in disease and the pathogenic potential of changes to the 3D genome.

Review Article | | Nature Reviews Genetics

The 4D Nucleome Network aims to map the spatial and dynamic organization of the human and mouse genomes to gain insight into the structure and biological functions of the nucleus.

Perspective | | Nature

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.

Review Article | | Nature Reviews Molecular Cell Biology

Three-dimensional genome organization can shape gene expression by facilitating interactions between regulatory elements. The authors review the process of X-chromosome inactivation with a focus on chromatin organization and subnuclear localization of the active and inactive X chromosomes, as well as the potential roles of long non-coding RNAs.

Review Article | | Nature Reviews Genetics

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.

Review Article | | Nature Reviews Molecular Cell Biology

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.

Review Article | | Nature Reviews Molecular Cell Biology

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.

Review Article | | Nature Reviews Genetics

Synthetic biology approaches to characterize gene regulation have largely used transcription factor circuits in bacteria. However, the multilayered regulation of genes by chromatin in eukaryotes provides opportunities for more sophisticated control of gene expression. This Review describes diverse approaches for engineering eukaryotic chromatin states, the insights gained into physiological gene regulation principles, and the broad potential applications throughout biomedical research and industry.

Review Article | | Nature Reviews Genetics

The evolution of genes is influenced by regional variation in mutation rates (RViMR). Chromatin organization affects RViMR, although the correlation between chromatin state and mutation types and rates is complex. This Review describes recent research on RViMR and chromatin organization, and the emerging findings from investigations of both germline and somatic mutations.

Review Article | | Nature Reviews Genetics

Promoter–enhancer loopings and other features of the 3D genome are dynamically regulated in the brain. In this Review, Akbarian and colleagues discuss how neuronal and glial gene expression is governed by the 3D genome, with implications for cognition and neuropsychiatric disease.

Review Article | | Nature Reviews Neuroscience

Research & Methods

The authors analyze time-resolved changes in genome topology, gene expression, transcription-factor binding, and chromatin state during iPSC generation. They conclude that 3D genome reorganization generally precedes gene expression changes and that removal of locus-specific topological barriers explains why pluripotency genes are activated sequentially during reprogramming.

Article | | Nature Genetics

Risk loci for breast cancer have been identified by genome-wide association studies. Here, the authors use Capture Hi-C to identify 110 putative target genes at 33 loci and assessed associations of gene expression, SNP genotype, and survival, providing evidence of mechanisms that may influence the prognosis and risk of breast cancer.

Article | open | | Nature Communications

Transcriptional regulation is coupled with chromosomal positioning and chromatin architecture. Here the authors develop a transcriptional decomposition approach to separate expression associated with genome structure from independent effects not directly associated with genomic positioning.

Article | open | | Nature Communications

Super-enhancers (SEs) are important regulatory elements for gene expression, but their intrinsic properties remain poorly understood. Here the authors analyse Hi-C and ChIP-seq data and find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers.

Article | open | | Nature Communications

Topologically associating domains (TADs) detected by Hi-C technologies are megabase-scale areas of highly interacting chromatin. Here Gong, Lazaris et al. develop a computational approach to improve the reproducibility of Hi-C contact matrices and stratify TAD boundaries based on their insulating strength.

Article | open | | Nature Communications

Depletion of chromosome-associated cohesin leads to loss of topologically associating domains in interphase chromosomes, without affecting segregation into compartments, and instead, it unmasks a finer compartment structure that reflects local chromatin and transcriptional activity.

Article | | Nature

High-resolution contact maps of active enhancers and target genes generated by H3K27ac HiChIP in primary human cells provide rational guides to link noncoding disease-associated risk variants to candidate causal genes. Genes are validated by CRISPR activation and interference at connected enhancers and eQTL analysis, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.

Article | | Nature Genetics

Proximity-ligation methods like Hi-C map DNA-DNA interactions and reveal its organization into topologically associating domains (TADs). Here the authors describe PSYCHIC, a computational approach for analysing Hi-C data that allows the identification of promoter-enhancer interactions.

Article | open | | Nature Communications

Metazoan genomes contain many clusters of conserved noncoding elements. Here, the authors provide evidence that these clusters coincide with distinct topologically associating domains in humans and Drosophila, revealing a conserved regulatory genomic architecture.

Article | open | | Nature Communications

Six tools to call chromatin interactions and seven tools for topologically associating domain calling are systematically compared with real and simulated data. The strengths and weaknesses of each tool are discussed.

Analysis | | Nature Methods

A chromosome conformation capture method in which single cells are first imaged and then processed enables intact genome folding to be studied at a scale of 100 kb, validated, and analysed to generate hypotheses about 3D genomic interactions and organisation.

Article | | Nature

Single-cell combinatorial indexed Hi-C (sciHi-C) is a streamlined protocol for generating thousands of high-quality single-cell chromosome conformation data sets that resemble bulk Hi-C data in aggregate.

Brief Communication | | Nature Methods

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.

Letter | | Nature

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.

Letter | | Nature

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.

Letter | | Nature

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.

Letter | | Nature

Michael Talkowski and colleagues analyze balanced chromosomal abnormalities in 273 individuals by whole-genome sequencing. Their findings suggest that sequence-level resolution improves prediction of clinical outcomes for balanced rearrangements and provides insight into pathogenic mechanisms such as altered gene regulation due to changes in chromosome topology.

Article | | Nature Genetics

Sean Whalen and colleagues present a computational method, TargetFinder, for reconstructing three-dimensional regulatory landscapes using one-dimensional genomic features. TargetFinder identifies the minimal set of features necessary to predict individual interacting enhancer–promoter pairs and accurately distinguishes them from non-interacting pairs.

Analysis | | Nature Genetics

José Luis Gómez-Skarmeta, Hector Escrivá, Ignacio Maeso, Damien Devos and colleagues perform 4C-seq profiling of the Hox cluster in amphioxus embryos and find that, unlike in vertebrate embryos, the cluster is organized into a single chromatin interaction domain. They suggest that the vertebrate Hox bipartite regulatory system is an evolutionary novelty.

Letter | | Nature Genetics

Sarah Elderkin and colleagues show that PRC1 acts as a master regulator of genome architecture in mouse embryonic stem cells by organizing genes in three-dimensional interaction networks. They find that the strongest spatial network is composed of the four Hox clusters and key early developmental transcription factor genes, and they propose that selective release of genes from this spatial network underlies cell fate specification during embryonic development.

Letter | | Nature Genetics

Douglas Higgs and colleagues functionally test the α-globin super-enhancer in mice by genetically deleting its constituent enhancers. They find that the individual regulatory elements seem to act independently and in an additive way with respect to hematological phenotype, gene expression, and chromatin structure and conformation.

Article | | Nature Genetics

Peter Scacheri and colleagues identify ‘outside’ SNPs that physically interact with GWAS risk SNPs as part of a target gene's regulatory circuitry. Their findings suggest a model whereby outside variants and GWAS SNPs that physically interact collude to influence target transcript levels as well as clinical risk.

Analysis | | Nature Genetics

Ken-ichi Noma and colleagues use ChIA-PET to identify genome-wide associations mediated by condensin and cohesin in fission yeast. They find that cohesin and condensin generate small and larger chromatin domains, respectively, and that condensin, but not cohesin, connects cell cycle–regulated genes bound by mitotic transcription factors.

Article | | Nature Genetics

Pooling barcoded 3C libraries and simultaneously capturing interactions at many loci of interest generates reproducible cis- and trans-interaction maps at high resolution from low amounts of input material. This allows for the comparison of interactions in different cell types using common software designed for differential analysis of sequence count data, rather than requiring software specifically designed for 3C experiments.

Article | | Nature Methods

Retroviruses such as HIV integrate into the host genome as an essential step prior to their replication. Here Lelek et al. identify nuclear pore complex proteins that are essential for HIV nuclear import and productive integration, and show that the intranuclear protein Tpr influences integration into transcriptionally active chromatin.

Article | open | | Nature Communications

Chromatin architecture is a key regulator of transcriptional processes, however current methods to investigate it have technical limitations. Here, the authors describe a novel chromatin capture technique, CATCH, which can be used to identify and characterize complex genomic interaction networks.

Article | open | | Nature Communications

Protocols

Ramani et al. describe a protocol for in situ DNase Hi-C as an alternative to traditional Hi-C methods that use restriction enzymes. The use of DNase I for chromatin digestion circumvents the resolution limit imposed when relying on genomic restriction sites.

Protocol | | Nature Protocols