Principles of Chromosome Architecture Revealed by Hi-C
Open accessAbstract
Chromosomes are folded and compacted in interphase nuclei, but the molecular basis of this folding is poorly understood. Chromosome conformation capture methods, such as Hi-C, combine chemical crosslinking of chromatin with fragmentation, DNA ligation, and high-throughput DNA sequencing to detect neighboring loci genome-wide. Hi-C has revealed the segregation of chromatin into active and inactive compartments and the folding of DNA into self-associating domains and loops. Depletion of CTCF, cohesin, or cohesin-associated proteins was recently shown to affect the majority of domains and loops in a manner that is consistent with a model of DNA folding through extrusion of chromatin loops. Compartmentation was not dependent on CTCF or cohesin. Hi-C contact maps represent the superimposition of CTCF/cohesin-dependent and -independent folding states.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
New methods have recently emerged that overcome many key limitations of earlier technologies, including single-cell methods, higher-resolution 3C, MPRAs, and high-throughput CRISPR screens.
“To this point, new methods have recently emerged that overcome many of the key limitations of earlier technologies. These include single-cell (‘sc’) methods to identify cell-type-specific open chromatin in complex tissues82,83; higher resolution chromosome conformation capture [G] methods to more finely map enhancer–promoter contacts84; MPRAs to dissect or trap enhancer activity on a reporter”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [84]
The Chromosome Compartmentation section (page unavailable) describes improved Hi-C resolution, and Chromatin Loops (page unavailable) explains that Hi-C contact maps reveal contacts between loci. The copy does not say that higher-resolution methods more finely map enhancer–promoter contacts. Citation 84 is attached to the chromosome-conformation-capture example, not to the separately cited single-cell methods, MPRAs, or CRISPR screens. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B. (2012) · Nature · doi:10.1038/nature11082 · Cited by 6,829 · see citing works
Spatial partitioning of the regulatory landscape of the X-inactivation centre
Nora, E. P., Lajoie, B. R., Schulz, E. G., Giorgetti, L., Okamoto, I., Servant, N., Piolot, T., van Berkum, N. L., Meisig, J., Sedat, J., et al. (2012) · Nature · doi:10.1038/nature11049 · Cited by 2,895 · see citing works
Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions
Lupiáñez, D. G., Kraft, K., Heinrich, V., Krawitz, P., Brancati, F., Klopocki, E., Horn, D., Kayserili, H., Opitz, J. M., Laxova, R., et al. (2015) · Cell · doi:10.1016/j.cell.2015.04.004 · Cited by 2,132 · see citing works
Formation of chromosomal domains by loop extrusion
Fudenberg, G., Imakaev, M., Lu, C., Goloborodko, A., Abdennur, N., & Mirny, L. A. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.085 · Cited by 2,003 · see citing works
Cohesin Loss Eliminates All Loop Domains
Rao, S. S. P., Huang, S.-C., Glenn St Hilaire, B., Engreitz, J. M., Perez, E. M., Kieffer-Kwon, K.-R., Sanborn, A. L., Johnstone, S. E., Bascom, G. D., Bochkov, I. D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.026 · Cited by 1,883 · see citing works
Sanborn, A. L., Rao, S. S. P., Huang, S.-C., Durand, N. C., Huntley, M. H., Jewett, A. I., Bochkov, I. D., Chinnappan, D., Cutkosky, A., Li, J., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1518552112 · Cited by 1,730 · see citing works
Nora, E. P., Goloborodko, A., Valton, A.-L., Gibcus, J. H., Uebersohn, A., Abdennur, N., Dekker, J., Mirny, L. A., & Bruneau, B. G. (2017) · Cell · doi:10.1016/j.cell.2017.05.004 · Cited by 1,709 · cited 5× · see citing works
“Auxin-mediated, acute protein degradation of CTCF [37,38] or cohesin [38,39] altered chromatin looping.”
BackgroundInfluentialInsulator dysfunction and oncogene activation in IDH mutant gliomas
Flavahan, W. A., Drier, Y., Liau, B. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., Suvà, M. L., & Bernstein, B. E. (2016) · Nature · doi:10.1038/nature16490 · Cited by 1,288 · see citing works
Two independent modes of chromatin organization revealed by cohesin removal
Schwarzer, W., Abdennur, N., Goloborodko, A., Pekowska, A., Fudenberg, G., Loe-Mie, Y., Fonseca, N. A., Huber, W., Haering, C. H., Mirny, L., et al. (2017) · Nature · doi:10.1038/nature24281 · Cited by 1,196 · see citing works
Activation of proto-oncogenes by disruption of chromosome neighborhoods
Hnisz, D., Weintraub, A. S., Day, D. S., Valton, A.-L., Bak, R. O., Li, C. H., Goldmann, J., Lajoie, B. R., Fan, Z. P., Sigova, A. A., et al. (2016) · Science · doi:10.1126/science.aad9024 · Cited by 1,042 · see citing works
Organization of the mitotic chromosome
Naumova, N., Imakaev, M., Fudenberg, G., Zhan, Y., Lajoie, B. R., Mirny, L. A., & Dekker, J. (2013) · Science · doi:10.1126/science.1236083 · Cited by 976 · cited 1× · see citing works
“Chromosomes undergo large conformational changes as cells divide [59,60].”
BackgroundCRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function
Guo, Y., Xu, Q., Canzio, D., Shou, J., Li, J., Gorkin, D. U., Jung, I., Wu, H., Zhai, Y., Tang, Y., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.038 · Cited by 958 · see citing works
Wutz, G., Várnai, C., Nagasaka, K., Cisneros, D. A., Stocsits, R. R., Tang, W., Schoenfelder, S., Jessberger, G., Muhar, M., Hossain, M. J., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201798004 · Cited by 864 · cited 9× · see citing works
“Auxin-mediated, acute protein degradation of CTCF [37,38] or cohesin [38,39] altered chromatin looping.”
BackgroundMethodInfluentialNasmyth, K. (2001) · Annual Review of Genetics · doi:10.1146/annurev.genet.35.102401.091334 · Cited by 805 · see citing works
The cohesin release factor WAPL restricts chromatin loop extension
Haarhuis, J. H. I., van der Weide, R. H., Blomen, V. A., Yáñez-Cuna, J. O., Amendola, M., van Ruiten, M. S., Krijger, P. H. L., Teunissen, H., Medema, R. H., van Steensel, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.04.013 · Cited by 793 · see citing works
Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells
Zuin, J., Dixon, J. R., van der Reijden, M. I. J. A., Ye, Z., Kolovos, P., Brouwer, R. W. W., van de Corput, M. P. C., van de Werken, H. J. G., Knoch, T. A., van IJcken, W. F. J., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1317788111 · Cited by 779 · see citing works
Formation of new chromatin domains determines pathogenicity of genomic duplications
Franke, M., Ibrahim, D. M., Andrey, G., Schwarzer, W., Heinrich, V., Schöpflin, R., Kraft, K., Kempfer, R., Jerković, I., Chan, W.-L., et al. (2016) · Nature · doi:10.1038/nature19800 · Cited by 673 · see citing works
CTCF Binding Polarity Determines Chromatin Looping
de Wit, E., Vos, E. S. M., Holwerda, S. J. B., Valdes-Quezada, C., Verstegen, M. J. A. M., Teunissen, H., Splinter, E., Wijchers, P. J., Krijger, P. H. L., & de Laat, W. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.09.023 · Cited by 641 · see citing works
Self-organization of domain structures by DNA-loop-extruding enzymes
Alipour, E., & Marko, J. F. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks925 · Cited by 540 · see citing works
Cohesin-mediated interactions organize chromosomal domain architecture
Sofueva, S., Yaffe, E., Chan, W., Georgopoulou, D., Vietri Rudan, M., Mira‐Bontenbal, H., Pollard, S. M., Schroth, G. P., Tanay, A., & Hadjur, S. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.237 · Cited by 394 · see citing works
Kundu, S., Ji, F., Sunwoo, H., Jain, G., Lee, J. T., Sadreyev, R. I., Dekker, J., & Kingston, R. E. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.009 · Cited by 333 · see citing works
Rapid movement and transcriptional re-localization of human cohesin on DNA
Davidson, I. F., Goetz, D., Zaczek, M. P., Molodtsov, M. I., Huis in 't Veld, P. J., Weissmann, F., Litos, G., Cisneros, D. A., Ocampo‐Hafalla, M., Ladurner, R., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201695402 · Cited by 246 · see citing works
Single-molecule imaging reveals a collapsed conformational state for DNA-bound cohesin
Stigler, J., Çamdere, G. Ö., Koshland, D. E., & Greene, E. C. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.003 · Cited by 229 · see citing works
Cohesin acetylation and Wapl-Pds5 oppositely regulate translocation of cohesin along DNA
Kanke, M., Tahara, E., Huis in't Veld, P. J., & Nishiyama, T. (2016) · The EMBO Journal · doi:10.15252/embj.201695756 · Cited by 136 · see citing works
Flagged first, then by citations
Research works printed but not linked: 42
- [1]Kornberg RD 1974 Chromatin structure: a repeating unit of histones and DNA Science 184 868 871 4825889
- [2]Luger K 1997 Crystal structure of the nucleosome core particle at 2.8 Å resolution Nature 389 251 260 9305837
- [3]Dekker J 2002 Capturing chromosome conformation Science 295 1306 1311 11847345
- [4]Lieberman-Aiden E 2009 Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome Science 326 289 293 19815776 PMC2858594
- [5]Rao SSP 2014 A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping Cell 159 1665 1680 25497547 PMC5635824
- [8]Sexton T 2012 Three-dimensional folding and functional organization principles of the Drosophila genome Cell 148 458 472 22265598
- [9]Rowley MJ 2017 Evolutionarily Conserved Principles Predict 3D Chromatin Organization Mol Cell 67 837 852e7 28826674 PMC5591081
- [10]Eagen KP 2015 Stable Chromosome Condensation Revealed by Chromosome Conformation Capture Cell 163 934 946 26544940 PMC4639323
- [11]Hochstrasser M 1986 Spatial organization of chromosomes in the salivary gland nuclei of Drosophila melanogaster J Cell Biol 102 112 123 3079766 PMC2114037
- [12]Wang S 2016 Spatial organization of chromatin domains and compartments in single chromosomes Science 353 598 602 27445307 PMC4991974
- [13]Gassler J 2017 A mechanism of cohesin-dependent loop extrusion organizes zygotic genome architecture EMBO J 10.15252/embj.201798083 PMC5730859 29217590 · DOI
- [14]Flyamer IM 2017 Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition Nature 544 110 114 28355183 PMC5639698
- [15]Eagen KP 2017 Polycomb-mediated chromatin loops revealed by a subkilobase-resolution chromatin interaction map Proceedings of the National Academy of Sciences 114 8764 8769 PMC5565414 28765367
- [16]Cubeñas-Potts C 2017 Different enhancer classes in Drosophila bind distinct architectural proteins and mediate unique chromatin interactions and 3D architecture Nucleic Acids Res 45 1714 1730 27899590 PMC5389536
- [17]Ulianov SV 2016 Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains Genome Res 26 70 84 26518482 PMC4691752
- [18]Stadler MR 2017 Convergence of topological domain boundaries, insulators, and polytene interbands revealed by high-resolution mapping of chromatin contacts in the early Drosophila melanogaster embryo elife 6 637662 PMC5739541 29148971
- [20]Beermann W 1972 Chromomeres and genes Results Probl Cell Differ 4 1 33 4198831
- [21]Szabo Q 2018 TADs are 3D structural units of higher-order chromosome organization in Drosophila Sci Adv 4 eaar8082 29503869 PMC5829972
- [22]Gligoris TG 2014 Closing the cohesin ring: structure and function of its Smc3-kleisin interface Science 346 963 967 25414305 PMC4300515
- [23]Huis in ‘t Veld PJ 2014 Characterization of a DNA exit gate in the human cohesin ring Science 346 968 972 25414306
- [24]Bell AC 1999 The protein CTCF is required for the enhancer blocking activity of vertebrate insulators Cell 98 387 396 10458613
- [25]Kim TH 2007 Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome Cell 128 1231 1245 17382889 PMC2572726
- [27]Uhlmann F 2016 SMC complexes: from DNA to chromosomes Nat Rev Mol Cell Biol 10.1038/nrm.2016.30 27075410 · DOI
- [28]Losada A 1998 Identification of Xenopus SMC protein complexes required for sister chromatid cohesion Genes Dev 12 1986 1997 9649503 PMC316973
- [29]Michaelis C 1997 Cohesins: chromosomal proteins that prevent premature separation of sister chromatids Cell 91 35 45 9335333
- [30]Guacci V 1997 A direct link between sister chromatid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae Cell 91 47 57 9335334 PMC2670185
- [31]Hirano T Mitchison TJ 1994 A heterodimeric coiled-coil protein required for mitotic chromosome condensation in vitro Cell 79 449 458 7954811
- [41]Seitan VC 2013 Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments Genome Res 23 2066 2077 24002784 PMC3847776
- [43]Ciosk R 2000 Cohesin’s binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins Mol Cell 5 243 254 10882066
- [44]Gandhi R 2006 Human Wapl is a cohesin-binding protein that promotes sister-chromatid resolution in mitotic prophase Curr Biol 16 2406 2417 17112726 PMC1850625
- [45]Kueng S 2006 Wapl controls the dynamic association of cohesin with chromatin Cell 127 955 967 17113138
- [48]Murayama Y Uhlmann F 2014 Biochemical reconstitution of topological DNA binding by the cohesin ring Nature 505 367 371 24291789 PMC3907785
- [49]Hou C 2012 Gene density, transcription, and insulators contribute to the partition of the Drosophila genome into physical domains Mol Cell 48 471 484 23041285 PMC3496039
- [51]Dong P 2017 3D chromatin architecture of large plant genomes determined by local A/B compartments Molecular Plant 10 1497 1509 29175436
- [52]Eichinger CS 2013 Disengaging the Smc3/kleisin interface releases cohesin from Drosophila chromosomes during interphase and mitosis EMBO J 32 656 665 23340528 PMC3590983
- [54]Terakawa T 2017 The condensin complex is a mechanochemical motor that translocates along DNA Science 11 eaan6516 PMC5862036 28882993
- [55]Hansen AS 2017 CTCF and cohesin regulate chromatin loop stability with distinct dynamics elife 6 e25776 28467304 PMC5446243
- [58]Ganji M 2018 Real-time imaging of DNA loop extrusion by condensin Science 10.1126/science.aar7831 PMC6329450 29472443 · DOI · Paper page
- [59]Gibcus JH 2018 A pathway for mitotic chromosome formation Science 359 eaao6135 29348367 PMC5924687
- [61]Nagano T 2017 Cell-cycle dynamics of chromosomal organization at single-cell resolution Nature 547 61 67 28682332 PMC5567812
- [62]Viny AD 2015 Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis J Exp Med 212 1819 1832 26438361 PMC4612085
- [67]Zhang Y 2012 Spatial organization of the mouse genome and its role in recurrent chromosomal translocations Cell 148 908 921 22341456 PMC3320767
Cited by
Sorted by citations
The senescence-associated secretory phenotype and its regulation
Lopes-Paciencia, S., Saint-Germain, E., Rowell, M.-C., Ruiz, A. F., Kalegari, P., & Ferbeyre, G. (2019) · Cytokine · doi:10.1016/j.cyto.2019.01.013 · Cited by 601 · see citing works
Towards a comprehensive catalogue of validated and target-linked human enhancers
Gasperini, M., Tome, J. M., & Shendure, J. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-019-0209-0 · Cited by 396 · see citing works
Hold out the genome: a roadmap to solving the cis-regulatory code
de Boer, C. G., & Taipale, J. (2024) · Nature · doi:10.1038/s41586-023-06661-w · Cited by 107 · see citing works
Sample-multiplexing approaches for single-cell sequencing
Zhang, Y., Xu, S., Wen, Z., Gao, J., Li, S., Weissman, S. M., & Pan, X. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04482-0 · Cited by 40 · see citing works
- Authors
- Eagen, K. P.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Eagen, Kyle P.
- ORCID
- Eagen, Kyle P.
- Venue
- Trends in Biochemical Sciences
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 43
- Issue
- 6
- Pages
- 469-478
- ISSN
- 0968-0004 (ISSN-L)
- PMC
- PMC6028237
- OpenAlex
- W2800185612
- Cited by
- 120
- References
- 24
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 14 · 2023: 20 · 2022: 12 · 2021: 21 · 2020: 15 · 2019: 18 · 2018: 4
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Biochemical Sciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DP5OD024587)
- 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 › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- chromosome organization, 3D genome organization, Hi-C, chromatin folding, CTCF, cohesin, chromatin compartments, topologically associating domains, chromatin looping, extrusion, interphase nuclei
- MeSH terms
- Animals, Chromosome Mapping, Chromosomes, Humans, Nucleic Acid Conformation, High-Throughput Nucleotide Sequencing
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
