CoChat
Sign Up
Cited by 976Genomics and Chromatin DynamicsAdvanced Fluorescence Microscopy TechniquesChromatin Remodeling and Cancer

Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells

Open access
Bintu, Bogdan, Mateo, Leslie J., Su, Jun-Han, Sinnott-Armstrong, Nicholas A., Parker, Mirae, Kinrot, Seon, Yamaya, Kei, Boettiger, Alistair N. +1 more·2018·Science
DOI 10.1126/science.aau1783PMC PMC6535145
Open this paper in CoChat — free accountOpen PDF

Abstract

Imaging chromatin spatial organization: The genome is organized within the nucleus as three-dimensional domains that modulate DNA-templated processes. Bintu et al. used high-throughput Oligopaint labeling and imaging to observe chromatin dynamics inside the nuclei of several different mammalian cell lines. After combining the datasets, single-cell matrices revealed chromatin arranged in topologically associating domains (TADs). Removing cohesin resulted in a loss of aggregate TADs among populations of cells, but specific TADs were still detected at the single-cell level. Furthermore, higher-order organization was detected, suggestive of cooperative interactions within the genome. Science , this issue p. eaau1783

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1126/science.aau1783

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Rapid depletion of cohesin or CTCF quickly abolishes TADs but has only relatively mild effects on gene expression.

    “rapid depletion of cohesin or CTCF quickly abolishes TADs but, as mentioned above, has only relatively mild effects on gene expression [301, 345–347, 448].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [448]

    The section “TAD-like structures remain in single cells after cohesin depletion” reports that six hours of induced cohesin degradation largely eliminated population-averaged TADs in the imaged regions. It does not report CTCF depletion or show that either depletion has only mild effects on gene expression. The paper also distinguishes the loss of population-averaged TADs from the persistence of TAD-like domains in single cells. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Single-cell studies show both substantial cell-to-cell heterogeneity of TADs and large numbers of inter-TAD chromosomal contacts.

    “single-cell studies show both a substantial cell-to-cell heterogeneity of TADs and large numbers of inter-TAD chromosomal contacts [448, 452].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [448]

    The section ‘Super-resolution chromatin tracing reveals TAD-like structures in single cells’ reports substantial cell-to-cell variation in TAD-like domain boundaries. It also describes extensive overlap between regions from different ensemble sub-TADs in one example cell, but does not establish large numbers of inter-TAD chromosomal contacts. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Advances in super-resolution imaging enable visualisation of multiple interacting loci to the resolution of a few kilobases in single cells.

    “advances in super-resolution imaging (reviewed in [500]) now enable the visualisation of multiple interacting loci to the resolution of a few kilobases in single cells [448, 501–503].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [448]

    The section “Multiplexed super-resolution FISH imaging for chromatin tracing” reports 3D super-resolution images of multiple chromatin segments in individual cells. Each segment spans 30 kb, however, so this paper does not support the claimed resolution of a few kilobases. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Enhancer-promoter contacts are stochastic and probably dynamic in single cells.

    “Enhancer–promoter contacts are stochastic32,37,38 and probably dynamic39 in single cells.”

    From Nonlinear control of transcription through enhancer–promoter interactions (2022) · cites this paper as [38]

    The section on cooperative, higher-order chromatin interactions reports that chromatin contacts vary from cell to cell, supporting the stochastic aspect of the claim. It does not establish that the variable contacts are specifically between enhancers and promoters. The paper’s Discussion suggests that single-cell domains may be dynamic, but does not demonstrate dynamic enhancer–promoter contacts. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • A recently developed oligopainting strategy combined with super-resolution microscopy allows the path of the chromatin fibril to be traced at relatively long genomic loci.

    “A recently developed oligopainting strategy [149] combined with super-resolution microscopy allows the path of the chromatin fibril to be traced at relatively long genomic loci [150,151].”

    From Enhancer Function in the 3D Genome (2023) · cites this paper as [150]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 56 · Cited by 976

Research works printed but not linked: 41

  1. [2]Levine M, Cattoglio C, Tjian R, Looping back to leap forward: Transcription enters a new era. Cell. 157, 13– 25 (2014). 24679523 PMC4059561
  2. [4]Dekker J, Mirny L, The 3D Genome as Moderator of Chromosomal Communication. Cell. 164, 1110– 1121 (2016). 26967279 PMC4788811
  3. [5]Krijger PHL, De Laat W, Regulation of disease-associated gene expression in the 3D genome. Nat. Rev. Mol. Cell Biol. 17, 771– 782 (2016). 27826147
  4. [6]Yu M, Ren B, The Three-Dimensional Organization of Mammalian Genomes. Annu. Rev. Cell Dev. Biol. 33, 265– 289 (2017). 28783961 PMC5837811
  5. [7]Lieberman-Aiden E, Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science (80-.). 326, 289– 293 (2009). PMC2858594 19815776
  6. [10]Sexton T, Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome. Cell. 148, 458– 472 (2012). 22265598
  7. [11]Hou C, Li L, Qin ZS, Corces VG, Gene Density, Transcription, and Insulators Contribute to the Partition of the Drosophila Genome into Physical Domains. Mol. Cell. 48, 471– 484 (2012). 23041285 PMC3496039
  8. [12]Rao SSP, A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping. Cell. 159, 1665– 1680 (2014). 25497547 PMC5635824
  9. [13]Phillips-Cremins JE, Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell. 153, 1281– 1295 (2013). 23706625 PMC3712340
  10. [14]Gibcus JH, Dekker J, The Hierarchy of the 3D Genome. Mol. Cell. 49, 773– 782 (2013). 23473598 PMC3741673
  11. [15]Sexton T, Cavalli G, The role of chromosome domains in shaping the functional genome. Cell. 160, 1049– 1059 (2015). 25768903
  12. [16]Boettiger AN, Super-resolution imaging reveals distinct chromatin folding for different epigenetic states. Nature. 529, 418– 422 (2016). 26760202 PMC4905822
  13. [17]Szabo Q, TADs are 3D structural units of higher-order chromosome organization in Drosophila. Sci. Adv. 4, 1– 14 (2018). PMC5829972 29503869
  14. [19]Flyamer IM, Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. Nature. 544, 110– 114 (2017). 28355183 PMC5639698
  15. [21]Nagano T, Cell-cycle dynamics of chromosomal organization at single-cell resolution. Nature. 547, 61– 67 (2017). 28682332 PMC5567812
  16. [23]Olivares-Chauvet P, Capturing pairwise and multi-way chromosomal conformations using chromosomal walks. Nature. 540, 296– 300 (2016). 27919068
  17. [24]Beagrie RA, Complex multi-enhancer contacts captured by genome architecture mapping. Nature. 543, 519– 524 (2017). 28273065 PMC5366070
  18. [26]Allahyar A, Enhancer hubs and loop collisions identified from single-allele topologies. Nat. Genet. 50, 1151– 1160 (2018). 29988121
  19. [28]Chen B, Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system. Cell. 155, 1479– 1491 (2013). 24360272 PMC3918502
  20. [29]Ricci MA, Manzo C, García-Parajo MF, Lakadamyali M, Cosma MP, Chromatin fibers are formed by heterogeneous groups of nucleosomes in vivo. Cell. 160, 1145– 1158 (2015). 25768910
  21. [30]Deng W, Shi X, Tjian R, Lionnet T, Singer RH, CASFISH: CRISPR/Cas9-mediated in situ labeling of genomic loci in fixed cells. Proc. Natl. Acad. Sci. 112, 11870– 11875 (2015). 26324940 PMC4586837
  22. [31]Ma H, Multiplexed labeling of genomic loci with dCas9 and engineered sgRNAs using CRISPRainbow. Nat. Biotechnol. 34, 528– 530 (2016). 27088723 PMC4864854
  23. [32]Chen KH, Boettiger AN, Moffitt JR, Wang S, Zhuang X, Spatially resolved, highly multiplexed RNA profiling in single cells. Science (80-.). 348 aaa6090 (2015). 10.1126/science.aaa6090 PMC4662681 25858977 · DOI · Paper page
  24. [33]Wang S, Spatial organization of chromatin domains and compartments in single chromosomes. Science (80-.). 353, 598– 602 (2016). PMC4991974 27445307
  25. [34]Beliveau BJ, Versatile design and synthesis platform for visualizing genomes with Oligopaint FISH probes. Proc. Natl. Acad. Sci. 109, 21301– 21306 (2012). 23236188 PMC3535588
  26. [35]Beliveau BJ, Single-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes. Nat. Commun. 6, 7147 (2015). 25962338 PMC4430122
  27. [36]Rust MJ, Bates M, Zhuang X, Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat. Methods. 3, 793– 795 (2006). 16896339 PMC2700296
  28. [37]Huang B, Wang W, Bates M, Zhuang X, Three-dimensional super-resolution imaging by stochastic optical reconstruction microscopy. Science (80-.). 319, 810– 813 (2008). PMC2633023 18174397
  29. [38]The ENCODE Project. Consortium, An integrated encyclopedia of DNA elements in the human genome. Nature. 489, 57– 74 (2012). 22955616 PMC3439153
  30. [42]Natsume T, Kiyomitsu T, Saga Y, Kanemaki MT, Rapid Protein Depletion in Human Cells by Auxin-Inducible Degron Tagging with Short Homology Donors. Cell Rep. 15, 210– 218 (2016). 27052166
  31. [45]Hnisz D, Shrinivas K, Young RA, Chakraborty AK, Sharp PA, A Phase Separation Model for Transcriptional Control. Cell. 169, 13– 23 (2017). 28340338 PMC5432200
  32. [46]Moffitt JR, High-throughput single-cell gene-expression profiling with multiplexed error-robust fluorescence in situ hybridization. Proc. Natl. Acad. Sci. 113, 11046– 11051 (2016). 27625426 PMC5047202
  33. [47]Bao W, Kojima KK, Kohany O, Repbase Update, a database of repetitive elements in eukaryotic genomes. Mob. DNA. 6, 11 (2015). doi: 10.1186/s13100-015-0041-9 26045719 PMC4455052 · DOI
  34. [49]Solovei I, Spatial preservation of nuclear chromatin architecture during three-dimensional fluorescence in situ hybridization (3D-FISH). Exp. Cell Res. 276, 10– 23 (2002). 11978004
  35. [50]Branco MR, Pombo A, Intermingling of chromosome territories in interphase suggests role in translocations and transcription-dependent associations. PLoS Biol. 4, 780– 788 (2006). PMC1440941 16623600
  36. [51]Markaki Y, The potential of 3D-FISH and super-resolution structured illumination microscopy for studies of 3D nuclear architecture: 3D structured illumination microscopy of defined chromosomal structures visualized by 3D (immuno)-FISH opens new perspectives for stud. BioEssays. 34, 412– 426 (2012). 22508100
  37. [52]Dempsey GT, A User’s Guide to Localization-Based Super-Resolution Fluorescence Imaging (Elsevier Inc, ed. 4, 2013; 10.1016/B978-0-12-407761-4.00024-5), vol. 114. 23931523 · DOI
  38. [53]Rasnik I, McKinney SA, Ha T, Nonblinking and long-lasting single-molecule fluorescence imaging. Nat. Methods. 3, 891– 893 (2006). 17013382
  39. [54]Matthiesen SH, Hansen CM, Fast and non-toxic in situ hybridization without blocking of repetitive sequences. PLoS One. 7, e40675 (2012). 10.1371/journal.pone.0040675 22911704 PMC3404051 · DOI
  40. [55]Machinek RRF, Ouldridge TE, Haley NEC, Bath J, Turberfield AJ, Programmable energy landscapes for kinetic control of DNA strand displacement. Nat. Commun. 5, 5324 (2014). doi: 10.1038/ncomms6324 25382214 · DOI
  41. [56]Babcock H, Sigal YM, Zhuang X, A high-density 3D localization algorithm for stochastic optical reconstruction microscopy. Opt. Nanoscopy. 1, 6 (2012). PMC4243665 25431749

Authors
Bintu, B., Mateo, L. J., Su, J.-H., Sinnott-Armstrong, N. A., Parker, M., Kinrot, S., Yamaya, K., Boettiger, A. N., & Zhuang, X.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Stanford University (US)
  • Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Corresponding author
  • Bintu, Bogdan
  • Mateo, Leslie J.
  • Boettiger, Alistair N.
  • Zhuang, Xiaowei
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2018-10-26
Volume
362
Issue
6413
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.aau1783
PMC
PMC6535145
OpenAlex
W2898514070
Cited by
976
References
56
Citations by year
2026: 81 · 2025: 131 · 2024: 112 · 2023: 104 · 2022: 127 · 2021: 156 · 2020: 136 · 2019: 118 · 2018: 10
FWCI
38.13
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
Funders
  • National Institutes of Health (R35GM122487)
  • Howard Hughes Medical Institute
  • Burroughs Wellcome Fund (CASI)
  • Chicago Community Trust (Searle Scholar)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
chromatin organization, topologically associating domains, chromatin conformation, single-cell imaging, super-resolution imaging, CTCF binding sites, cohesin, domain boundaries, 3D genome organization
MeSH terms
Protein Domains, CCCTC-Binding Factor, Cohesins, Chromatin, Chromosomal Proteins, Non-Histone, Humans, Protein Binding, Genome, Human, In Situ Hybridization, Fluorescence, Cell Cycle Proteins, HCT116 Cells, Single-Cell Analysis

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