CoChat
Sign Up
Cited by 25Genomics and Chromatin DynamicsChromatin Remodeling and CancerGene Regulatory Network Analysis

Dynamic enhancer function in the chromatin context

Open access
Goldstein, Ido, Hager, Gordon L.·2018·WIREs Systems Biology and Medicine
DOI 10.1002/wsbm.1390PMC PMC6638546
Open this paper in CoChat — free account

Abstract

Enhancers serve as critical regulatory elements in higher eukaryotic cells. The characterization of enhancer function has evolved primarily from genome‐wide methodologies, including chromatin immunoprecipitation (ChIP‐seq), DNase‐I hypersensitivity (DNase‐seq), digital genomic footprinting (DGF), and the chromosome conformation capture techniques (3C, 4C, and Hi‐C). These population‐based assays average signals across millions of cells and lead to enhancer models characterized by static and sequential binding. More recently, fluorescent microscopy techniques, including fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, and single molecule tracking (SMT), reveal a highly dynamic binding behavior for these factors in live cells. Furthermore, a refined analysis of genomic footprinting suggests that many transcription factors leave minimal or no footprints in chromatin, even when present and active in a given cell type. In this study, we review the implications of these new approaches for an accurate understanding of enhancer function in real time. In vivo SMT, in particular, has recently evolved as a promising methodology to probe enhancer function in live cells. Integration of findings from the many approaches now employed in the study of enhancer function suggest a highly dynamic view for the action of enhancer activating factors, viewed on a time scale of milliseconds to seconds, rather than minutes to hours. WIREs Syst Biol Med 2018, 10:e1390. doi: 10.1002/wsbm.1390 This article is categorized under: Analytical and Computational Methods > Computational Methods Laboratory Methods and Technologies > Genetic/Genomic Methods Laboratory Methods and Technologies > Imaging

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 · 10.1002/wsbm.1390

Cites

16 of 16 references verified0 citation errors · 0 not checkable

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?

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

Flagged first, then by citations

Research works printed but not linked: 70

  1. [1]Gruss P, Dhar R, Khoury G. Simian virus 40 tandem repeated sequences as an element of the early promoter. Proc Natl Acad Sci USA 1981, 78: 943– 7. 6262784 PMC319921
  2. [2]Benoist C, Chambon P. In vivo sequence requirements of the SV40 early promotor region. Nature 1981, 290: 304– 10. 6259538
  3. [3]Banerji J, Rusconi S, Schaffner W. Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell 1981, 27: 299– 308. 6277502
  4. [4]Liu Z, Merkurjev D, Yang F, Li W, Oh S, Friedman MJ, Song X, Zhang F, Ma Q, Ohgi KA, Enhancer activation requires trans-recruitment of a mega transcription factor complex. Cell 2014, 159: 358– 373. 25303530 PMC4465761
  5. [5]Mueller F, Stasevich TJ, Mazza D, McNally JG. Quantifying transcription factor kinetics: at work or at play? Crit Rev Biochem Mol Biol 2013, 48: 492– 514. 24025032
  6. [6]Thanos D, Maniatis T. Virus induction of human IFN beta gene expression requires the assembly of an enhanceosome. Cell 1995, 83: 1091– 1100. 8548797
  7. [7]Neph S, Vierstra J, Stergachis AB, Reynolds AP, Haugen E, Vernot B, Thurman RE, John S, Sandstrom R, Johnson AK, An expansive human regulatory lexicon encoded in transcription factor footprints. Nature 2012, 489: 83– 90. 22955618 PMC3736582
  8. [8]Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, Epstein CB, Frietze S, Harrow J, Kaul R, An integrated encyclopedia of DNA elements in the human genome. Nature 2012, 489: 57– 74. 22955616 PMC3439153
  9. [10]Ørom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G, Lai F, Zytnicki M, Notredame C, Huang Q, Long noncoding RNAs with enhancer-like function in human cells. Cell 2010, 143: 46– 58. 20887892 PMC4108080
  10. [11]Wang D, Garcia-Bassets I, Benner C, Li W, Su X, Zhou Y, Qiu J, Liu W, Kaikkonen MU, Ohgi KA, Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 2011, 474: 390– 394. 21572438 PMC3117022
  11. [12]Orom UA, Shiekhattar R. Noncoding RNAs and enhancers: complications of a long-distance relationship. Trends Genet 2011, 27: 433– 439. 21831473 PMC4484734
  12. [13]Mousavi K, Zare H, Dell’orso S, Grontved L, Gutierrez-Cruz G, Derfoul A, Hager GL, Sartorelli V. eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci. Mol Cell 2013, 51: 606– 617. 23993744 PMC3786356
  13. [14]Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, Ren B. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 2012, 485: 376– 380. 22495300 PMC3356448
  14. [15]Lupiáñez DG, Kraft K, Heinrich V, Krawitz P, Brancati F, Klopocki E, Horn D, Kayserili H, Opitz JM, Laxova R, Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 2015, 161: 1012– 25. 25959774 PMC4791538
  15. [16]Lupianez DG, Spielmann M, Mundlos S. Breaking TADs: how alterations of chromatin domains result in disease. Trends Genet 2016, 32: 225– 37. 26862051
  16. [17]Dekker J, Rippe K, Dekker M, Kleckner N. Capturing chromosome conformation. Science 2002, 295: 1306– 1311. 11847345
  17. [19]Van BK, Corces VG. Lost in transition: dynamic enhancer organization across naive and primed stem cell states. Cell Stem Cell 2014, 14: 693– 694. 24905156 PMC4115280
  18. [20]Plank JL, Dean A. Enhancer function: mechanistic and genome-wide insights come together. Mol Cell 2014, 55: 5– 14. 24996062 PMC8441652
  19. [21]Shiekhattar R Opening the chromatin by eRNAs. Mol Cell 2013, 51: 557– 558. 24034693 PMC4492513
  20. [22]Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, Hoke HA, Young RA. Super-enhancers in the control of cell identity and disease. Cell 2013, 155: 934– 947. 24119843 PMC3841062
  21. [23]Denker A, de Laat W. The second decade of 3C technologies: detailed insights into nuclear organization. Genes Dev 2016, 30: 1357– 82. 27340173 PMC4926860
  22. [24]Rinn JL, Chang HY. Genome regulation by long non-coding RNAs. Annu Rev Biochem 2012, 81: 145– 66. 22663078 PMC3858397
  23. [25]Rivera CM, Ren B. Mapping human epigenomes. Cell 2013, 155: 39– 55. 24074860 PMC3838898
  24. [26]Shlyueva D, Stampfel G, Stark A. Transcriptional enhancers: from properties to genome-wide predictions. Nat Rev Genet 2014, 15: 272– 286. 24614317
  25. [27]Boyle AP, Davis S, Shulha HP, Meltzer P, Margulies EH, Weng Z, Furey TS, Crawford GE. High-resolution mapping and characterization of open chromatin across the genome. Cell 2008, 132: 311– 322. 18243105 PMC2669738
  26. [28]Oliveri M, Daga A, Lunardi C, Navone R, Millo R, Puccetti A. DNase I behaves as a transcription factor which modulates Fas expression in human cells. Eur J Immunol 2004, 34: 273– 9. 14971053
  27. [29]Grøntved L, Bandle R, John S, Baek S, Chung HJ, Liu Y, Aguilera G, Oberholtzer C, Hager GL, Levens D. Rapid genome-scale mapping of chromatin accessibility in tissue. Epigenetics Chromatin 2012, 5: 1– 12. 22734930 PMC3464876
  28. [30]Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, Panhuis TM, Mieczkowski P, Secchi A, Bosco D, A map of open chromatin in human pancreatic islets. Nat Genet 2010, 42: 255– 259. 20118932 PMC2828505
  29. [31]Chen PB, Zhu LJ, Hainer SJ, McCannell KN, Fazzio TG. Unbiased chromatin accessibility profiling by RED-seq uncovers unique features of nucleosome variants in vivo. BMC Genomics 2014, 15: 1104. 25494698 PMC4378318
  30. [32]Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods 2013, 10: 1213– 1218. 24097267 PMC3959825
  31. [33]Buenrostro JD, Wu B, Litzenburger UM, Ruff D, Gonzales ML, Snyder MP, Chang HY, Greenleaf WJ. Single-cell chromatin accessibility reveals principles of regulatory variation. Nature 2015, 23: 523. PMC4685948 26083756
  32. [34]Galas DJ, Schmitz A. DNAse footprinting: a simple method for the detection of protein-DNA binding specificity. Nucleic Acids Res 1978, 5: 3157– 3170. 212715 PMC342238
  33. [35]Sung MH, Baek S, Hager GL. Genome-wide footprinting: ready for prime time? Nat Methods 2016, 13: 222– 8. 26914206 PMC5140282
  34. [36]Baek S, Sung MH. Genome-scale analysis of cell-specific regulatory codes using nuclear enzymes. Methods Mol Biol 2016, 1418: 225– 40. 27008018 PMC5142241
  35. [39]Sung MH, Guertin MJ, Baek S, Hager GL. DNase footprint signatures are dictated by factor dynamics and DNA sequence. Mol Cell 2014, 56: 275– 285. 25242143 PMC4272573
  36. [40]Yardimci GG, Frank CL, Crawford GE, Ohler U. Explicit DNase sequence bias modeling enables high-resolution transcription factor footprint detection. Nucleic Acids Res 2014, 42: 11865– 78. 25294828 PMC4231734
  37. [42]Groeneweg FL, van Royen ME, Fenz S, Keizer VI, Geverts B, Prins J, de Kloet ER, Houtsmuller AB, Schmidt TS, Schaaf MJ. Quantitation of glucocorticoid receptor DNA-binding dynamics by single-molecule microscopy and FRAP. PLoS One 2014, 9: e90532. 24632838 PMC3954550
  38. [43]Qiu Y, Stavreva DA, Luo Y, Indrawan A, Chang M, Hager GL. Dynamic interaction of HDAC1 with a glucocorticoid receptor regulated gene is modulated by the activity state of the promoter. J Biol Chem 2011, 286: 7641– 7647. 21127047 PMC3045018
  39. [44]Meijsing SH, Elbi C, Luecke HF, Hager GL, Yamamoto KR. The ligand binding domain controls glucocorticoid receptor dynamics independent of ligand release. Mol Cell Biol 2007, 27: 2442– 2451. 17261597 PMC1899895
  40. [45]Rayasam GV, Elbi C, Walker DA, Wolford R, Fletcher TM, Edwards DP, Hager GL. Ligand specific dynamics of the progesterone receptor in living cells and during chromatin remodeling in vitro. Mol Cell Biol 2005, 25: 2406– 2418. 15743833 PMC1061598
  41. [46]Agresti A, Scaffidi P, Riva A, Caiolfa VR, Bianchi ME. GR and HMGB1 interact only within chromatin and influence each other’s residence time. Mol Cell 2005, 18: 109– 121. 15808513
  42. [48]Coulon A, Chow CC, Singer RH, Larson DR. Eukaryotic transcriptional dynamics: from single molecules to cell populations. Nat Rev Genet 2013, 14: 572– 584. 23835438 PMC3807637
  43. [50]Hager GL, McNally JG, Misteli T. Transcription dynamics. Mol Cell 2009, 35: 741– 753. 19782025 PMC6326382
  44. [51]van Royen ME, Zotter A, Ibrahim SM, Geverts B, Houtsmuller AB. Nuclear proteins: finding and binding target sites in chromatin. Chromosome Res 2011, 19: 83– 98. 21181254
  45. [52]Mazza D, Abernathy A, Golob N, Morisaki T, McNally JG. A benchmark for chromatin binding measurements in live cells. Nucleic Acids Res 2012, 40: e119. 22844090 PMC3424588
  46. [53]Mazza D, Mueller F, Stasevich TJ, McNally JG. Convergence of chromatin binding estimates in live cells. Nat Methods 2013, 10: 691– 692. 23900248
  47. [54]Los GV, Encell LP, McDougall MG, Hartzell DD, Karassina N, Zimprich C, Wood MG, Learish R, Ohana RF, Urh M. HaloTag: a novel protein labeling technology for cell imaging and protein analysis. ACS Chem Biol 2008, 3: 373– 382. 18533659
  48. [55]Gautier A, Juillerat A, Heinis C, Corrêa IR Jr, Kindermann M, Beaufils F, Johnsson K. An engineered protein tag for multiprotein labeling in living cells. Chem Biol 2008, 15: 128– 136. 18291317
  49. [56]Grimm JB, English BP, Chen J, Slaughter JP, Zhang Z, Revyakin A, Patel R, Macklin JJ, Normanno D, Singer RH. A general method to improve fluorophores for live-cell and single-molecule microscopy. Nat Methods 2015, 12: 244– 250. 25599551 PMC4344395
  50. [57]Tokunaga M, Imamoto N, Sakata-Sogawa K. Highly inclined thin illumination enables clear single-molecule imaging in cells. Nat Methods 2008, 5: 159– 161. 18176568
  51. [58]Elf J, Li GW, Xie XS. Probing transcription factor dynamics at the single-molecule level in a living cell. Science 2007, 316: 1191– 1194. 17525339 PMC2853898
  52. [59]Gebhardt JCM, Suter DM, Roy R, Zhao ZW, Chapman AR, Basu S, Maniatis T, Xie XS. Single-molecule imaging of transcription factor binding to DNA in live mammalian cells. Nat Methods 2013, 10: 421– 426. 23524394 PMC3664538
  53. [60]Morisaki T, Muller WG, Golob N, Mazza D, McNally JG. Single-molecule analysis of transcription factor binding at transcription sites in live cells. Nat Commun 2014, 5: 4456. 25034201 PMC4144071
  54. [61]Liu Z, Legant WR, Chen B-C, Li L, Grimm JB, Lavis LD, Betzig E, Tjian R. 3D imaging of Sox2 enhancer clusters in embryonic stem cells. Elife 2014, 3: e04236. 25537195 PMC4381973
  55. [63]Izeddin I, Récamier V, Bosanac L, Cissé II, Boudarene L, Dugast-Darzacq C, Proux F, Bénichou O, Voituriez R, Bensaude O. Single-molecule tracking in live cells reveals distinct target-search strategies of transcription factors in the nucleus. Elife 2014, 3: e02230. PMC4095940 24925319
  56. [64]van Royen ME, van Cappellen WA, Geverts B, Schmidt T, Houtsmuller AB, Schaaf MJ. Androgen receptor complexes probe DNA for recognition sequences by short random interactions. J Cell Sci 2014, 127: 1406– 1416. 24481814
  57. [65]Sugo N, Morimatsu M, Arai Y, Kousoku Y, Ohkuni A, Nomura T, Yanagida T, Yamamoto N. Single-molecule imaging reveals dynamics of CREB transcription factor bound to its target sequence. Sci Rep 2015, 5: 10662. 26039515 PMC4454023
  58. [66]Speil J, Baumgart E, Siebrasse J-P, Veith R, Vinkemeier U, Kubitscheck U. Activated STAT1 transcription factors conduct distinct saltatory movements in the cell nucleus. Biophys J 2011, 101: 2592– 2600. 22261046 PMC3297778
  59. [67]Coleman RA, Liu Z, Darzacq X, Tjian R, Singer RH, Lionnet T. Imaging transcription: past, present, and future. Cold Spring Harb Symp Quant Biol 2015, 80: 1– 8. 26763984 PMC4915995
  60. [68]Swinstead EE, Miranda TB, Paakinaho V, Baek S, Goldstein I, Hawkins M, Karpova TS, Ball D, Mazza D, Lavis LD. Steroid receptors reprogram FoxA1 occupancy through dynamic chromatin transitions. Cell 2016, 165: 593– 605. 27062924 PMC4842147
  61. [70]Presman DM, Ball DA, Paakinaho V, Grimm JB, Lavis LD, Karpova TS, Hager GL. Quantifying transcription factor dynamics at the single-molecule level in live cells. Methods 2017, 116: 1– 13. 28315485 PMC5522764
  62. [71]Liu Z, Lavis LD, Betzig E. Imaging live-cell dynamics and structure at the single-molecule level. Mol Cell 2015, 58: 644– 659. 26000849
  63. [73]Biddie SC, John S, Sabo PJ, Thurman RE, Johnson TA, Schiltz RL, Miranda TB, Sung MH, Trump S, Lightman SL, Vinson C, Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol Cell 2011, 43: 145– 155. 21726817 PMC3138120
  64. [74]Grøntved L, John S, Baek S, Liu Y, Buckley JR, Vinson C, Aguilera G, Hager GL. C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. EMBO J 2013, 32: 1568– 1583. 23665916 PMC3671252
  65. [79]Chen H, Larson DR. What have single-molecule studies taught us about gene expression? Genes Dev 2016, 30: 1796– 810. 27601529 PMC5024679
  66. [81]Gusmao EG, Allhoff M, Zenke M, Costa IG. Analysis of computational footprinting methods for DNase sequencing experiments. Nat Methods 2016, 13: 303– 309. 26901649
  67. Coulon A, Chow CC, Singer RH, Larson DR. Eukaryotic transcriptional dynamics: from single molecules to cell populations. Nat Rev Genet 2013, 14: 572– 584. 23835438 PMC3807637
  68. Voss TC, Hager GL. Dynamic regulation of transcriptional states by chromatin and transcription factors. Nat Rev Genet 2014, 15: 69– 81. 24342920 PMC6322398
  69. Swinstead EE, Paakinaho V, Presman DM, Hager GL. Pioneer factors and ATP-dependent chromatin remodeling factors interact dynamically: a new perspective. Multiple transcription factors can effect chromatin pioneer functions through dynamic interactions with ATP-dependent chromatin remodeling factors. Bioessays 2016, 38: 1150– 1157. 27633730 PMC6319265
  70. Lupianez DG, Spielmann M, Mundlos S. Breaking TADs: how alterations of chromatin domains result in disease. Trends Genet 2016, 32: 225– 237. 26862051

Cited by

Sorted by citations

Authors
Goldstein, I., & Hager, G. L.
Affiliations
National Institutes of Health (US)
Corresponding author
Hager, Gordon L.
ORCID
Venue
WIREs Systems Biology and Medicine
Publisher
Wiley
Published
2017-05-22
Volume
10
Issue
1
ISSN
  • 1939-005X (ISSN-L)
  • 1939-5094
DOI
10.1002/wsbm.1390
PMC
PMC6638546
OpenAlex
W2619138019
Cited by
25
References
16
Citations by year
2026: 2 · 2025: 1 · 2024: 3 · 2023: 3 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 4 · 2017: 2
FWCI
0.33
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • WIREs Systems Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute
  • Council for Chemical Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
enhancers, enhancer function, single-molecule tracking, live-cell imaging, chromatin, genomic footprinting, chromatin conformation, enhancer regulation
MeSH terms
Chromatin, DNA, Enhancer Elements, Genetic, Humans, Protein Binding, Transcription Factors, Genome

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