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3D structures of individual mammalian genomes studied by single-cell Hi-C
Open accessAbstract
The folding of genomic DNA from the beads-on-a-string-like structure of nucleosomes into higher-order assemblies is crucially linked to nuclear processes. Here we calculate 3D structures of entire mammalian genomes using data from a new chromosome conformation capture procedure that allows us to first image and then process single cells. The technique enables genome folding to be examined at a scale of less than 100 kb, and chromosome structures to be validated. The structures of individual topological-associated domains and loops vary substantially from cell to cell. By contrast, A and B compartments, lamina-associated domains and active enhancers and promoters are organized in a consistent way on a genome-wide basis in every cell, suggesting that they could drive chromosome and genome folding. By studying genes regulated by pluripotency factor and nucleosome remodelling deacetylase (NuRD), we illustrate how the determination of single-cell genome structure provides a new approach for investigating biological processes.
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“In regard to chromatin structure, Stevens and colleagues reported that the combination of chromosome conformation capture (3C) and tagged fluorescent imaging was able to detect the folding of a genomic sequence <100bp in a single cell (303).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [303]
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“Currently, single-cell Hi-C studies confirm the presence of TADs in individual cells but demonstrate significant variability in their shape (i.e., in the folding of DNA within TADs) [142,143,144,145].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [144]
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Computational 3D genome modeling using Chrom3D
Paulsen, J., Ali, T. M. L., & Collas, P. (2018) · Nature Protocols · doi:10.1038/nprot.2018.009 · Cited by 55
“In the mouse, a subset of LADs also seem to associate with the nucleolus, in the nuclear interior 32 .”
BackgroundRačko, D., Benedetti, F., Dorier, J., & Stasiak, A. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1091 · Cited by 58
“The ‘hallmarks’ of the loop extrusion process, which are clearly visible in Hi-C contact maps of mammalian cells are focal peaks resulting from prolonged direct contacts between two borders of a given TAD (60,61).”
BackgroundInfluentialThe role of nuclear matrix protein HNRNPU in maintaining the architecture of 3D genome
Zhang, L., Song, D., Zhu, B., & Wang, X. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.07.006 · Cited by 57
The biology and polymer physics underlying large‐scale chromosome organization
Sazer, S., & Schießel, H. (2017) · Traffic · doi:10.1111/tra.12539 · Cited by 54
Yu, J., Peng, J., & Chi, H. (2019) · Current Opinion in Systems Biology · doi:10.1016/j.coisb.2019.03.003 · Cited by 61
“…cytometry or CyTOF, NanoLC-MS) [37,38], genome [39], and chromatin accessibility or epigenome (scATAC-seq, scChIP-seq, scBS-seq, scHi-C) [40,41,42,43,44] has provided an unprecedented opportunity to overcome this challenge by simultaneously quantifying molecular features at the single-cell…”
BackgroundGene regulation on extrachromosomal DNA
Hung, K. L., Mischel, P. S., & Chang, H. Y. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00806-7 · Cited by 56
3D genome and its disorganization in diseases
Li, R., Liu, Y., Hou, Y., Gan, J., Wu, P., & Cheng, L. (2018) · Cell Biology and Toxicology · doi:10.1007/s10565-018-9430-4 · Cited by 56
Three-dimensional organization and dynamics of the genome
Szałaj, P., & Plewczyński, D. (2018) · Cell Biology and Toxicology · doi:10.1007/s10565-018-9428-y · Cited by 59
“Genomewide, there is a high correlation between gene expression level and its localization in respect to CT surface and its depth within compartment A (Stevens et al. 2017; Peric-Hupkes et al. 2010).”
BackgroundResultInfluentialVistain, L. F., Phan, H. V., Keisham, B., Jordi, C., Chen, M., Reddy, S. T., & Tay, S. (2022) · Nature Methods · doi:10.1038/s41592-022-01684-z · Cited by 57
Multiscale structure of chromatin condensates explains phase separation and material properties
Zhou, H., Huertas, J., Maristany, M. J., Russell, K. O., Hwang, J. H., Yao, R.-W., Samanta, N., Hutchings, J., Billur, R., Shiozaki, M., et al. (2025) · Science · doi:10.1126/science.adv6588 · Cited by 61
Understanding the kidney one cell at a time
Park, J., Liu, C., Kim, J., & Suszták, K. (2019) · Kidney International · doi:10.1016/j.kint.2019.03.035 · Cited by 53
“Methods for single cell histone chromatin immunoprecipitation (ChIP-Seq)[14], open chromatin area (ATAC-Seq; Assay for Transposase-Accessible Chromatin using sequencing)[15],[16], DNA methylation[17],[18] and 3-D chromatin organization (such single cell Hi-C)[19],[20], have been developed.”
MethodChallenges and guidelines toward 4D nucleome data and model standards
Martí-Renom, M. A., Almouzni, G., Bickmore, W. A., Bystricky, K., Cavalli, G., Fraser, P., Gasser, S. M., Giorgetti, L., Heard, É., Nicodemi, M., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0236-3 · Cited by 53
“The main experimental data driving these models come from 3C-based experiments, including single-cell Hi-C 84–87 , as well as imaging 88 .”
de Wit, E. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.09.026 · Cited by 57
Physical and data structure of 3D genome
Huang, K., Li, Y., Shim, A. R., Nap, R. J., Agrawal, V., Virk, R. K. A., Eshein, A., Almassalha, L. M., Backman, V., & Szleifer, I. G. (2020) · Science Advances · doi:10.1126/sciadv.aay4055 · Cited by 54
“1), a minimal model is able to pivot a wide array of chromatin features including untangled compaction (25), disordered morphology (3), nonglobular territory (30), porous nuclear medium (45), biphasic chromatin mass scaling (27, 28), abundance of nanoclusters or clutches (22), non-Gaussian domain size distribution (42…”
BackgroundResultInfluentialJavasky, E., Shamir, I., Gandhi, S., Egri, S. B., Sandler, O., Rothbart, S. B., Kaplan, N., Jaffe, J. D., Goren, A., & Simon, I. (2018) · Genome Research · doi:10.1101/gr.230300.117 · Cited by 56
“Recently, genome-wide long-range interactionswithinmitotic chromosomes were investigated by Hi-C and 4C (Naumova et al. 2013; Dileep et al. 2015; Stevens et al. 2017).”
BackgroundRegulation of Chromatin Structure During Neural Development
Kishi, Y., & Gotoh, Y. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00874 · Cited by 51
“Given the heterogeneity of NPCs and neurons, analyses at the single-cell level will be especially important for studies of neural development, and the recent implementation of advanced single-cell RNA-seq, ChIP-seq, DamID, ATAC-seq, and Hi-C technologies should prove highly informative in this regard (Nagano et al., 2…”
MethodChromatin Remodelers in the 3D Nuclear Compartment
Magaña‐Acosta, M., & Valadéz-Graham, V. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.600615 · Cited by 58
3D chromatin architecture and epigenetic regulation in cancer stem cells
Feng, Y., Liu, X., & Pauklin, S. (2021) · Protein & Cell · doi:10.1007/s13238-020-00819-2 · Cited by 55
Spatial Features and Functional Implications of Plant 3D Genome Organization
Domb, K., Wang, N., Hummel, G., & Liu, C. (2022) · Annual Review of Plant Biology · doi:10.1146/annurev-arplant-102720-022810 · Cited by 54
Boninsegna, L., Yıldırım, A., Polles, G., Zhan, Y., Quinodoz, S. A., Finn, E. H., Guttman, M., Zhou, X. J., & Alber, F. (2022) · Nature Methods · doi:10.1038/s41592-022-01527-x · Cited by 48
Normalization and de-noising of single-cell Hi-C data with BandNorm and scVI-3D
Zheng, Y., Shen, S., & Keleş, S. (2022) · Genome biology · doi:10.1186/s13059-022-02774-z · Cited by 52
Single cell epigenome sequencing technologies
Wen, L., & Tang, F. (2017) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2017.09.002 · Cited by 51
Reconstructing spatial organizations of chromosomes through manifold learning
Zhu, G., Deng, W., Hu, H., Ma, R., Zhang, S., Yang, J., Peng, J., Kaplan, T., & Zeng, J. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky065 · Cited by 49
“Several stochastic sampling based methods, such as Markov chain Monte Carlo (MCMC) and simulated annealing (32), were also used in a probabilistic framework to compute chromatin structures that satisfy the spatial distances derived from Hi-C data.”
Network Approaches for Dissecting the Immune System
Shi, H., Yan, K., Ding, L., Qian, C., Chi, H., & Yu, J. (2020) · iScience · doi:10.1016/j.isci.2020.101354 · Cited by 51
The 3D Genome Structure of Single Cells
Zhou, T., Zhang, R., & Ma, J. (2021) · Annual Review of Biomedical Data Science · doi:10.1146/annurev-biodatasci-020121-084709 · Cited by 51
“Indeed, several computational approaches have been developed (33, 35, 92–94).”
BackgroundMethodXu, H., Zhang, S., Yi, X., Plewczyński, D., & Li, M. J. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.02.013 · Cited by 48
“To describe the highly dynamic 3D chromatin at single cells, several groups have optimized the 3C-based techniques and applied them to track chromatin conformation on single cells across different development stages and conditions [94–98].”
MethodSingle-cell Hi-C data analysis: safety in numbers
Galitsyna, A. A., & Gelfand, M. S. (2021) · Briefings in Bioinformatics · doi:10.1093/bib/bbab316 · Cited by 47
“In read clipping, reads are scanned for the restriction site [69, 82] or bridge adapter [76], and all the 3′ sequences after the match are removed.”
BackgroundMethodInfluentialAnalyzing Circulating Tumor Cells One at a Time
Ortiz, V., & Yu, M. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.05.004 · Cited by 48
“Moreover, in scHi-C analysis, mitotic cells have shown disappearance of topologically associating domains and chromosomal A(active) and B (inactive) compartments, showing dramatic reorganization of the genomic structures during cell division [62].”
BackgroundMethodChromatin topology in development and disease
Bompadre, O., & Andrey, G. (2019) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2019.04.007 · Cited by 47
Ji, H. Y., Uyan, Ö., Yan, K., Liu, T., Zhu, Q., Tóthová, Z., Botten, G. A., Xu, J., Yuan, G., Dekker, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26574-4 · Cited by 49
Kriz, A. J., Colognori, D., Sunwoo, H., Nabet, B., & Lee, J. T. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.02.031 · Cited by 46
Epigenetics in the modern era of crop improvements
Xue, Y., Cao, X., Chen, X., Deng, X. M., Deng, X. W., Ding, Y., Dong, A., Duan, C., Fang, X., Gong, L., et al. (2025) · Science China Life Sciences · doi:10.1007/s11427-024-2784-3 · Cited by 52
“…organization, known as the chromosome territory, has been observed through both fluorescence in situ hybridization (FISH) and high-throughput chromosome conformation capture (Hi-C) experiments (Bintu et al., 2018; Cremer and Cremer, 2001; Lieberman-Aiden et al., 2009; Stevens et al., 2017).”
Metadata
- Authors
- Stevens, T. J., Lando, D., Basu, S., Atkinson, L. P., Cao, Y., Lee, S. F., Leeb, M., Wohlfahrt, K. J., Boucher, W., O’Shaughnessy-Kirwan, A., Cramard, J., Faure, A. J., Ralser, M., Blanco, E., Morey, L., Sansó, M., Palayret, M. G. S., Lehner, B., Di Croce, L., Wutz, A., Hendrich, B., Klenerman, D., & Laue, E. D.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- University of Cambridge (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- European Molecular Biology Laboratory (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Laue, Ernest D.
- ORCID
- Venue
- Nature
- Published
- 2017-03-13
- Volume
- 544
- Issue
- 7648
- Pages
- 59-64
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5385134
- OpenAlex
- W2597274540
- Cited by
- 832
- References
- 41
- Citations by year
- 2026: 42 · 2025: 73 · 2024: 62 · 2023: 71 · 2022: 95 · 2021: 115 · 2020: 95 · 2019: 121 · 2018: 99 · 2017: 58
- FWCI
- 41.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust (082010/Z/07/Z, 277899, 206291/Z/17/Z, 082010)
- Medical Research Council (MR/M010082/1, MC_PC_12009, MR/P019471/1)
- Cancer Research UK Cambridge Institute, University of Cambridge
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Keywords
- 3D genome organization, single-cell Hi-C, chromosome conformation capture, topologically associating domains, chromatin looping, lamina-associated domains, mouse embryonic stem cells, cell-to-cell variability, pluripotency factors, nucleosome remodeling, nuclear organization
- MeSH terms
- Mouse Embryonic Stem Cells, CCCTC-Binding Factor, Cohesins, Animals, Chromosomal Proteins, Non-Histone, DNA, Enhancer Elements, Genetic, Gene Expression Regulation, Haploidy, Models, Molecular, Molecular Conformation, Nucleosomes, Promoter Regions, Genetic, Repressor Proteins, Reproducibility of Results, G1 Phase, Genome, Cell Cycle Proteins, Chromosomes, Mammalian, Chromatin Assembly and Disassembly, Mice, Gene Regulatory Networks, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Molecular Imaging, Single-Cell Analysis
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