CoChat
Sign Up
Cited by 929Genomics and Chromatin DynamicsChromatin Remodeling and CancerEpigenetics and DNA Methylation

Enhancer function: new insights into the regulation of tissue-specific gene expression

Open access
Ong, Chin-Tong, Corces, Victor G.·2011·Nature Reviews Genetics
DOI 10.1038/nrg2957PMC PMC3175006
Open this paper in CoChat — free account

Abstract

Enhancer function underlies regulatory processes by which cells establish patterns of gene expression. Recent results suggest that many enhancers are specified by particular chromatin marks in pluripotent cells, which may be modified later in development to alter patterns of gene expression and cell differentiation choices. These marks may contribute to the repertoire of epigenetic mechanisms responsible for cellular memory and determine the timing of transcription factor accessibility to the enhancer. Mechanistically, cohesin and non-coding RNAs are emerging as crucial players responsible for facilitating enhancer-promoter interactions at some genes. Surprisingly, these interactions may be required not only to facilitate initiation of transcription but also to activate the release of RNA polymerase II (RNAPII) from promoter-proximal pausing.

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 · 10.1038/nrg2957

Cites

14 of 14 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?

  • Gene transcription is often influenced by TF occupancy at multiple enhancer regions.

    “Gene transcription is often influenced by TF occupancy at multiple enhancer regions (Ong and Corces, 2011).”

    From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Ong and Corces, 2011

    The opening section says enhancers contain transcription-factor binding sites and that enhancer-bound factors help activate transcription. The long-range interactions section describes multiple enhancer elements interacting with promoters at the Th2 cytokine locus. These passages support the mechanism and an example involving multiple enhancers, but do not establish that transcription is often influenced by factor occupancy at multiple enhancer regions. (LLM, conf=0.78)

    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

Flagged first, then by citations

Research works printed but not linked: 80

  1. [1]Levine M Transcriptional enhancers in animal development and evolution Curr Biol 20 R754 63 20833320 PMC4280268
  2. [3]Banerji J Rusconi S Schaffner W Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences Cell 27 299 308 1981 6277502
  3. [4]Geyer PK Green MM Corces VG Tissue-specific transcriptional enhancers may act in trans on the gene located in the homologous chromosome: the molecular basis of transvection in Drosophila EMBO J 9 2247 56 1990 2162766 PMC551949
  4. [5]Lomvardas S Interchromosomal interactions and olfactory receptor choice Cell 126 403 13 2006 16873069
  5. [6]Haugen SP Ross W Gourse RL Advances in bacterial promoter recognition and its control by factors that do not bind DNA Nat Rev Microbiol 6 507 19 2008 18521075 PMC3700611
  6. [7]Malik S Roeder RG The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation Nat Rev Genet 11 761 72 20940737 PMC3217725
  7. [8]Schoenfelder S Clay I Fraser P The transcriptional interactome: gene expression in 3D Curr Opin Genet Dev 20 127 33 20211559
  8. [9]Clapier CR Cairns BR The biology of chromatin remodeling complexes Annu Rev Biochem 78 273 304 2009 19355820
  9. [11]Cui KR Chromatin Signatures in Multipotent Human Hematopoietic Stem Cells Indicate the Fate of Bivalent Genes during Differentiation Cell Stem Cell 4 80 93 2009 19128795 PMC2785912
  10. [13]Orom UA Long noncoding RNAs with enhancer-like function in human cells Cell 143 46 58 20887892 PMC4108080
  11. [14]Zippo A Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation Cell 138 1122 36 2009 19766566
  12. [15]Ruthenburg AJ Li H Patel DJ Allis CD Multivalent engagement of chromatin modifications by linked binding modules Nature Reviews Molecular Cell Biology 8 983 994 2007 PMC4690530 18037899
  13. [16]Henikoff S Nucleosome destabilization in the epigenetic regulation of gene expression Nature Reviews Genetics 9 15 26 2008 18059368
  14. [17]Mito Y Henikoff JG Henikoff S Histone replacement marks the boundaries of cis-regulatory domains Science 315 1408 1411 2007 17347439
  15. [18]Lee W A high- resolution atlas of nucleosome occupancy in yeast Nature Genetics 39 1235 1244 2007 17873876
  16. [19]Mavrich TN Nucleosome organization in the Drosophila genome Nature 453 358 U27 2008 18408708 PMC2735122
  17. [21]Schones DE Dynamic regulation of nucleosome positioning in the human genome Cell 132 887 898 2008 18329373 PMC10894452
  18. [22]Albert I Translational and rotational settings of H2A.Z nucleosomes across the Saccharomyces cerevisiae genome Nature 446 572 576 2007 17392789
  19. [23]Henikoff S Henikoff JG Sakai A Loeb GB Ahmad K Genome-wide profiling of salt fractions maps physical properties of chromatin Genome Research 19 460 469 2009 19088306 PMC2661814
  20. [24]Jin CY Felsenfeld G Nucleosome stability mediated by histone variants H3.3 and H2A.Z Genes & Development 21 1519 1529 2007 17575053 PMC1891429
  21. [26]Jin CY H3.3/H2A.Z double variant-containing nucleosomes mark ‘nucleosome-free regions’ of active promoters and other regulatory regions Nature Genetics 41 941 U112 2009 19633671 PMC3125718
  22. [27]He HSHS Nucleosome dynamics define transcriptional enhancers Nature Genetics 42 343 U101 2010 20208536 PMC2932437
  23. [28]Lin YC A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate Nature Immunology 11 635 U109 2010 20543837 PMC2896911
  24. [29]Bedford DC Kasper LH Fukuyama T Brindle PK Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases Epigenetics 5 9 15 20110770 PMC2829352
  25. [30]Birney E Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project Nature 447 799 816 2007 17571346 PMC2212820
  26. [31]Visel A ChIP-seq accurately predicts tissue-specific activity of enhancers Nature 457 854 858 2009 19212405 PMC2745234
  27. [32]Blow MJ ChIP-Seq identification of weakly conserved heart enhancers Nature Genetics 42 806 U107 2010 20729851 PMC3138496
  28. [33]Lupien M FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription Cell 132 958 970 2008 18358809 PMC2323438
  29. [34]Crawford GE Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS) Genome Research 16 123 131 2006 16344561 PMC1356136
  30. [35]Roh TY Cuddapah S Zhao K Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping Genes & Development 19 542 552 2005 15706033 PMC551575
  31. [36]Roh TY Wei G Farrell CM Zhao K Genome-wide prediction of conserved and nonconserved enhancers by histone acetylation patterns Genome Research 17 74 81 2007 17135569 PMC1716270
  32. [37]Mizuguchi G ATP-Driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex Science 303 343 348 2004 14645854
  33. [39]Vastenhouw NL Chromatin signature of embryonic pluripotency is established during genome activation Nature 464 922 U143 2010 20336069 PMC2874748
  34. [40]Liber D Epigenetic priming of a pre-B cell-specific enhancer through binding of Sox2 and Foxd3 at the ESC stage Cell Stem Cell 7 114 26 20621055
  35. [41]Drane P Ouararhni K Depaux A Shuaib M Hamiche A The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3 Genes & Development 24 1253 1265 2010 20504901 PMC2885661
  36. [42]Goldberg AD Distinct Factors Control Histone Variant H3.3 Localization at Specific Genomic Regions Cell 140 678 691 2010 20211137 PMC2885838
  37. [43]Lewis PW Elsaesser SJ Noh KM Stadler SC Allis CD Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres Proceedings of the National Academy of Sciences of the United States of America 107 14075 14080 2010 20651253 PMC2922592
  38. [44]Hartley PD Madhani HD Mechanisms that Specify Promoter Nucleosome Location and Identity Cell 137 445 458 2009 19410542 PMC2677553
  39. [45]Orford K Differential H3K4 methylation identifies developmentally poised hematopoietic genes Dev Cell 14 798 809 2008 18477461 PMC10948009
  40. [46]Kleinjan DA van Heyningen V Long-range control of gene expression: emerging mechanisms and disruption in disease Am J Hum Genet 76 8 32 2005 15549674 PMC1196435
  41. [47]Engel JD Tanimoto K Looping, linking, and chromatin activity: new insights into beta-globin locus regulation Cell 100 499 502 2000 10721987
  42. [48]Bulger M Groudine M Looping versus linking: toward a model for long-distance gene activation Genes Dev 13 2465 77 1999 10521391
  43. [49]Sexton T Bantignies F Cavalli G Genomic interactions: chromatin loops and gene meeting points in transcriptional regulation Semin Cell Dev Biol 20 849 55 2009 19559093
  44. [50]Phillips JE Corces VG CTCF: Master Weaver of the Genome Cell 137 1194 1211 2009 19563753 PMC3040116
  45. [51]West AG Fraser P Remote control of gene transcription Hum Mol Genet 14 Spec No 1 R101 11 2005 15809261
  46. [52]Chambeyron S Bickmore WA Does looping and clustering in the nucleus regulate gene expression? Curr Opin Cell Biol 16 256 62 2004 15145349
  47. [53]Dekker J Rippe K Dekker M Kleckner N Capturing chromosome conformation Science 295 1306 11 2002 11847345
  48. [54]Simonis M Kooren J de Laat W An evaluation of 3C-based methods to capture DNA interactions Nature Methods 4 895 901 2007 17971780
  49. [56]Miele A Dekker J Mapping cis- and trans- chromatin interaction networks using chromosome conformation capture (3C) Methods Mol Biol 464 105 21 2009 18951182 PMC3874836
  50. [57]Miele A Dekker J Long-range chromosomal interactions and gene regulation Mol Biosyst 4 1046 57 2008 18931780 PMC2653627
  51. [58]Bulger M Groudine M Enhancers: the abundance and function of regulatory sequences beyond promoters Dev Biol 339 250 7 20025863 PMC3060611
  52. [59]Drissen R The active spatial organization of the beta-globin locus requires the transcription factor EKLF Genes Dev 18 2485 90 2004 15489291 PMC529536
  53. [60]Vakoc CR Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1 Mol Cell 17 453 62 2005 15694345
  54. [61]Spilianakis CG Flavell RA Long-range intrachromosomal interactions in the T helper type 2 cytokine locus Nat Immunol 5 1017 27 2004 15378057
  55. [62]Cai S Lee CC Kohwi-Shigematsu T SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes Nat Genet 38 1278 88 2006 17057718
  56. [63]Schoenfelder S Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells Nature Genetics 42 53 U71 2010 20010836 PMC3237402
  57. [64]Michaelis C Ciosk R Nasmyth K Cohesins: chromosomal proteins that prevent premature separation of sister chromatids Cell 91 35 45 1997 9335333
  58. [65]Guacci V Koshland D Strunnikov A A direct link between sister chromatid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae Cell 91 47 57 1997 9335334 PMC2670185
  59. [66]Nasmyth K Haering CH The structure and function of SMC and kleisin complexes Annu Rev Biochem 74 595 648 2005 15952899
  60. [67]Rollins RA Morcillo P Dorsett D Nipped-B, a Drosophila homologue of chromosomal adherins, participates in activation by remote enhancers in the cut and Ultrabithorax genes Genetics 152 577 93 1999 10353901 PMC1460629
  61. [68]Rollins RA Korom M Aulner N Martens A Dorsett D Drosophila nipped-B protein supports sister chromatid cohesion and opposes the stromalin/Scc3 cohesion factor to facilitate long-range activation of the cut gene Mol Cell Biol 24 3100 11 2004 15060134 PMC381657
  62. [69]Dorsett D Effects of sister chromatid cohesion proteins on cut gene expression during wing development in Drosophila Development 132 4743 53 2005 16207752 PMC1635493
  63. [70]Schuldiner O piggyBac-based mosaic screen identifies a postmitotic function for cohesin in regulating developmental axon pruning Dev Cell 14 227 38 2008 18267091 PMC2268086
  64. [71]Pauli A Cell-type-specific TEV protease cleavage reveals cohesin functions in Drosophila neurons Dev Cell 14 239 51 2008 18267092 PMC2258333
  65. [72]Horsfield JA Cohesin-dependent regulation of Runx genes Development 134 2639 49 2007 17567667
  66. [73]Parelho V Cohesins functionally associate with CTCF on mammalian chromosome arms Cell 132 422 33 2008 18237772
  67. [75]Stedman W Cohesins localize with CTCF at the KSHV latency control region and at cellular c-myc and H19/Igf2 insulators EMBO J 27 654 66 2008 18219272 PMC2262040
  68. [77]Mishiro T Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster EMBO J 28 1234 45 2009 19322193 PMC2683055
  69. [78]Hadjur S Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus Nature 460 410 U130 2009 19458616 PMC2869028
  70. [79]Nativio R Cohesin is required for higher-order chromatin conformation at the imprinted IGF2-H19 locus PLoS Genet 5 e1000739 2009 19956766 PMC2776306
  71. [80]Hou C Dale R Dean A Cell type specificity of chromatin organization mediated by CTCF and cohesin Proc Natl Acad Sci U S A 107 3651 6 20133600 PMC2840441
  72. [83]Lei EP Corces VG RNA interference machinery influences the nuclear organization of a chromatin insulator Nat Genet 38 936 41 2006 16862159
  73. [84]Yao H Mediation of CTCF transcriptional insulation by DEAD-box RNA-binding protein p68 and steroid receptor RNA activator SRA Genes Dev PMC2975930 20966046
  74. [86]Yamamoto Y Verma UN Prajapati S Kwak YT Gaynor RB Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression Nature 423 655 9 2003 12789342
  75. [87]Ivaldi MS Karam CS Corces VG Phosphorylation of histone H3 at Ser10 facilitates RNA polymerase II release from promoter-proximal pausing in Drosophila Genes Dev 21 2818 31 2007 17942706 PMC2045134
  76. [88]Zippo A De Robertis A Serafini R Oliviero S PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation Nat Cell Biol 9 932 44 2007 17643117
  77. [89]Karam CS Kellner WA Takenaka N Clemmons AW Corces VG 14-3-3 mediates histone cross-talk during transcription elongation in Drosophila PLoS Genet 6 e1000975 20532201 PMC2880557
  78. [90]Core LJ Lis JT Transcription regulation through promoter-proximal pausing of RNA polymerase II Science 319 1791 2 2008 18369138 PMC2833332
  79. [91]Bajpai R CHD7 cooperates with PBAF to control multipotent neural crest formation Nature 463 958 U135 2010 20130577 PMC2890258
  80. [92]Cheng X Blumenthal RM Coordinated chromatin control: structural and functional linkage of DNA and histone methylation Biochemistry 49 2999 3008 20210320 PMC2857722

Cited by

Sorted by citations

Authors
Ong, C.-T., & Corces, V. G.
Affiliations
Emory University (US)
Corresponding author
Corces, Victor G.
ORCID
Venue
Nature Reviews Genetics
Publisher
Springer Science and Business Media LLC
Published
2011-03-01
Volume
12
Issue
4
Pages
283-293
ISSN
  • 1471-0056 (ISSN-L)
  • 1471-0064
DOI
10.1038/nrg2957
PMC
PMC3175006
OpenAlex
W1965425724
Cited by
929
References
14
Citations by year
2026: 20 · 2025: 47 · 2024: 46 · 2023: 58 · 2022: 59 · 2021: 75 · 2020: 63 · 2019: 67 · 2018: 67 · 2017: 58 · 2016: 63 · 2015: 63 · 2014: 79 · 2013: 71 · 2012: 70
FWCI
7.00
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Science Foundation
  • National Institute of General Medical Sciences (GM-35463, R01GM035463)
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 › Epigenetics and DNA Methylation
Keywords
enhancer function, tissue-specific gene expression, chromatin modification, cohesin, non-coding RNA, enhancer-promoter interactions, epigenetic regulation, cell differentiation, RNA polymerase II pausing, pluripotent cells
MeSH terms
Animals, Cell Differentiation, Chromatin, Enhancer Elements, Genetic, Humans, Promoter Regions, Genetic, RNA Polymerase II, Gene Expression, Pluripotent Stem Cells, Epigenomics

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