1932

Abstract

Cell-type- and condition-specific profiles of gene expression require coordination between protein-coding gene promoters and -regulatory sequences called enhancers. Enhancers can stimulate gene activity at great genomic distances from their targets, raising questions about how enhancers communicate with specific gene promoters and what molecular mechanisms underlie enhancer function. Characterization of enhancer loci has identified the molecular features of active enhancers that accompany the binding of transcription factors and local opening of chromatin. These characteristics include coactivator recruitment, histone modifications, and noncoding RNA transcription. However, it remains unclear which of these features functionally contribute to enhancer activity. Here, we discuss what is known about how enhancers regulate their target genes and how enhancers and promoters communicate. Further, we describe recent data demonstrating many similarities between enhancers and the gene promoters they control, and we highlight unanswered questions in the field, such as the potential roles of transcription at enhancers.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-011420-095916
2020-06-20
2024-06-24
Loading full text...

Full text loading...

/deliver/fulltext/biochem/89/1/annurev-biochem-011420-095916.html?itemId=/content/journals/10.1146/annurev-biochem-011420-095916&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Serfling E, Jasin M, Schaffner W 1985. Enhancers and eukaryotic gene transcription. Trends Genet 1:224–30
    [Google Scholar]
  2. 2. 
    Banerji J, Rusconi S, Schaffner W 1981. Expression of a β-globin gene is enhanced by remote SV40 DNA sequences. Cell 27:2299–308
    [Google Scholar]
  3. 3. 
    Banerji J, Olson L, Schaffner W 1983. A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. Cell 33:3729–40
    [Google Scholar]
  4. 4. 
    Gillies SD, Morrison SL, Oi VT, Tonegawa S 1983. A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene. Cell 33:3717–28
    [Google Scholar]
  5. 5. 
    Heinz S, Romanoski CE, Benner C, Glass CK 2015. The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol. 16:3144–54
    [Google Scholar]
  6. 6. 
    Zaret KS. 2018. Pioneering the chromatin landscape. Nat. Genet. 50:2167–69
    [Google Scholar]
  7. 7. 
    Fernandez Garcia M, Moore CD, Schulz KN, Alberto O, Donague G et al. 2019. Structural features of transcription factors associating with nucleosome binding. Mol. Cell 75:5921–32
    [Google Scholar]
  8. 8. 
    Roeder RG. 2005. Transcriptional regulation and the role of diverse coactivators in animal cells. FEBS Lett 579:4909–15
    [Google Scholar]
  9. 9. 
    Weake VM, Workman JL. 2010. Inducible gene expression: diverse regulatory mechanisms. Nat. Rev. Genet. 11:6426–37
    [Google Scholar]
  10. 10. 
    Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM et al. 2010. Widespread transcription at neuronal activity-regulated enhancers. Nature 465:7295182–87
    [Google Scholar]
  11. 11. 
    de Santa F, Barozzi I, Mietton F, Ghisletti S, Polletti S et al. 2010. A large fraction of extragenic RNA Pol II transcription sites overlap enhancers. PLOS Biol 8:5e1000384
    [Google Scholar]
  12. 12. 
    Beck DB, Oda H, Shen SS, Reinberg D 2012. PR-Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Genes Dev 26:4325–37
    [Google Scholar]
  13. 13. 
    Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A et al. 2009. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459:7243108–12
    [Google Scholar]
  14. 14. 
    Visel A, Blow MJ, Li Z, Zhang T, Akiyama JA et al. 2009. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457:7231854–58
    [Google Scholar]
  15. 15. 
    Johnson DS, Mortazavi A, Myers RM, Wold B 2012. An integrated encyclopedia of DNA elements in the human genome. Nature 489:741457–74
    [Google Scholar]
  16. 16. 
    Shen Y, Yue F, McCleary DF, Ye Z, Edsall L et al. 2012. A map of the cis-regulatory sequences in the mouse genome. Nature 488:7409116–20
    [Google Scholar]
  17. 17. 
    Frankel N, Davis GK, Vargas D, Wang S, Payre F, Stern DL 2010. Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature 466:7305490–93
    [Google Scholar]
  18. 18. 
    Osterwalder M, Barozzi I, Tissiéres V, Fukuda-Yuzawa Y, Mannion BJ et al. 2018. Enhancer redundancy provides phenotypic robustness in mammalian development. Nature 554:7691239–43
    [Google Scholar]
  19. 19. 
    De Laat W, Duboule D 2013. Topology of mammalian developmental enhancers and their regulatory landscapes. Nature 502:7472499–506
    [Google Scholar]
  20. 20. 
    Bulger M, Groudine M. 2011. Functional and mechanistic diversity of distal transcription enhancers. Cell 144:3327–39
    [Google Scholar]
  21. 21. 
    Ghavi-Helm Y, Klein FA, Pakozdi T, Ciglar L, Noordermeer D et al. 2014. Enhancer loops appear stable during development and are associated with paused polymerase. Nature 512:751296–100
    [Google Scholar]
  22. 22. 
    Sanyal A, Lajoie BR, Jain G, Dekker J 2012. The long-range interaction landscape of gene promoters. Nature 489:7414109–13
    [Google Scholar]
  23. 23. 
    Rao SSP, Huntley MH, Durand NC, Stamenova EK, Bochkov ID et al. 2014. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159:71665–80
    [Google Scholar]
  24. 24. 
    Fulco CP, Munschauer M, Anyoha R, Munson G, Grossman SR et al. 2016. Systematic mapping of functional enhancer-promoter connections with CRISPR interference. Science 354:6313769–73
    [Google Scholar]
  25. 25. 
    Bonev B, Mendelson Cohen N, Szabo Q, Fritsch L, Papadopoulos GL et al. 2017. Multiscale 3D genome rewiring during mouse neural development. Cell 171:3557–72
    [Google Scholar]
  26. 26. 
    Kvon EZ, Kazmar T, Stampfel G, Yáñez-Cuna JO, Pagani M et al. 2014. Genome-scale functional characterization of Drosophila developmental enhancers in vivo. Nature 512:191–95
    [Google Scholar]
  27. 27. 
    Lettice LA, Heaney SJH, Purdie LA, Li L, de Beer P et al. 2003. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Mol. Genet. 12:141725–35
    [Google Scholar]
  28. 28. 
    Freire-Pritchett P, Schoenfelder S, Várnai C, Wingett SW, Cairns J et al. 2017. Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells. eLife 6:e21926
    [Google Scholar]
  29. 29. 
    Parker SCJ, Stitzel ML, Taylor DL, Orozco JM, Erdos MR et al. 2013. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. PNAS 110:4417921–26
    [Google Scholar]
  30. 30. 
    Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V et al. 2013. Super-enhancers in the control of cell identity and disease. Cell 155:4934–47
    [Google Scholar]
  31. 31. 
    Moorthy SD, Davidson S, Shchuka VM, Singh G, Malek-Gilani N et al. 2017. Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes. Genome Res 27:2246–58
    [Google Scholar]
  32. 32. 
    Hay D, Hughes JR, Babbs C, Davies JOJ, Graham BJ et al. 2016. Genetic dissection of the α-globin super-enhancer in vivo. Nat. Genet. 48:8895–903
    [Google Scholar]
  33. 33. 
    Barakat TS, Halbritter F, Zhang M, Rendeiro AF, Perenthaler E et al. 2018. Functional dissection of the enhancer repertoire in human embryonic stem cells. Cell Stem Cell 23:2276–88
    [Google Scholar]
  34. 34. 
    Yáñez-Cuna JO, Arnold CD, Stampfel G, Boryń ŁM, Gerlach D et al. 2014. Dissection of thousands of cell type-specific enhancers identifies dinucleotide repeat motifs as general enhancer features. Genome Res 24:71147–56
    [Google Scholar]
  35. 35. 
    Navratilova P, Fredman D, Hawkins TA, Turner K, Lenhard B, Becker TS 2009. Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes. Dev. Biol. 327:2526–40
    [Google Scholar]
  36. 36. 
    Inoue F, Ahituv N. 2015. Decoding enhancers using massively parallel reporter assays. Genomics 106:3159–64
    [Google Scholar]
  37. 37. 
    Patwardhan RP, Lee C, Litvin O, Young DL, Pe'er D, Shendure J 2009. High-resolution analysis of DNA regulatory elements by synthetic saturation mutagenesis. Nat. Biotechnol. 27:121173–75
    [Google Scholar]
  38. 38. 
    Arnold CD, Gerlach D, Stelzer C, Boryń ŁM, Rath M, Stark A 2013. Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science 339:61231074–77
    [Google Scholar]
  39. 39. 
    Zabidi MA, Arnold CD, Schernhuber K, Pagani M, Rath M et al. 2015. Enhancer-core-promoter specificity separates developmental and housekeeping gene regulation. Nature 518:7540556–59
    [Google Scholar]
  40. 40. 
    Muerdter F, Boryń ŁM, Woodfin AR, Neumayr C, Rath M et al. 2018. Resolving systematic errors in widely used enhancer activity assays in human cells. Nat. Methods 15:2141–49
    [Google Scholar]
  41. 41. 
    O'Kane CJ, Gehring WJ. 1987. Detection in situ of genomic regulatory elements in Drosophila. PNAS 84:249123–27
    [Google Scholar]
  42. 42. 
    Kokubu C, Horie K, Abe K, Ikeda R, Mizuno S et al. 2009. A transposon-based chromosomal engineering method to survey a large cis-regulatory landscape in mice. Nat. Genet. 41:8946–52
    [Google Scholar]
  43. 43. 
    Ruf S, Symmons O, Uslu VV, Dolle D, Hot C et al. 2011. Large-scale analysis of the regulatory architecture of the mouse genome with a transposon-associated sensor. Nat. Genet. 43:4379–87
    [Google Scholar]
  44. 44. 
    Pickar-Oliver A, Gersbach CA. 2019. The next generation of CRISPR-Cas technologies and applications. Nat. Rev. Mol. Cell Biol. 20:8490–507
    [Google Scholar]
  45. 45. 
    Rajagopal N, Srinivasan S, Kooshesh K, Guo Y, Edwards MD et al. 2016. High-throughput mapping of regulatory DNA. Nat. Biotechnol. 34:2167–74
    [Google Scholar]
  46. 46. 
    Sanjana NE, Wright J, Zheng K, Shalem O, Fontanillas P et al. 2016. High-resolution interrogation of functional elements in the noncoding genome. Science 353:63071545–49
    [Google Scholar]
  47. 47. 
    Diao Y, Fang R, Li B, Meng Z, Yu J et al. 2017. A tiling-deletion-based genetic screen for cis-regulatory element identification in mammalian cells. Nat. Methods 14:6629–35
    [Google Scholar]
  48. 48. 
    Kosicki M, Tomberg K, Bradley A 2018. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat. Biotechnol. 36:8765–71
    [Google Scholar]
  49. 49. 
    Haapaniemi E, Botla S, Persson J, Schmierer B, Taipale J 2018. CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nat. Med. 24:7927–30
    [Google Scholar]
  50. 50. 
    Ihry RJ, Worringer KA, Salick MR, Frias E, Ho D et al. 2018. p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat. Med. 24:7939–46
    [Google Scholar]
  51. 51. 
    Kearns NA, Genga RMJ, Enuameh MS, Garber M, Wolfe SA, Maehr R 2013. Cas9 effector-mediated regulation of transcription and differentiation in human pluripotent stem cells. Development 141:1219–23
    [Google Scholar]
  52. 52. 
    Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA et al. 2013. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154:2442–51
    [Google Scholar]
  53. 53. 
    Klann TS, Black JB, Chellappan M, Safi A, Song L et al. 2017. CRISPR-Cas9 epigenome editing enables high-throughput screening for functional regulatory elements in the human genome. Nat. Biotechnol. 35:6561–68
    [Google Scholar]
  54. 54. 
    Xie S, Duan J, Li B, Zhou P, Hon GC 2017. Multiplexed engineering and analysis of combinatorial enhancer activity in single cells. Mol. Cell 66:2285–99
    [Google Scholar]
  55. 55. 
    Gasperini M, Hill AJ, McFaline-Figueroa JL, Martin B, Kim S et al. 2019. A genome-wide framework for mapping gene regulation via cellular genetic screens. Cell 176:1–2377–90
    [Google Scholar]
  56. 56. 
    Song SH, Kim AR, Ragoczy T, Bender MA, Groudine M, Dean A 2010. Multiple functions of Ldb1 required for β-globin activation during erythroid differentiation. Blood 116:132356–64
    [Google Scholar]
  57. 57. 
    Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ 2013. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10:121213–18
    [Google Scholar]
  58. 58. 
    Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW et al. 2007. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39:3311–18
    [Google Scholar]
  59. 59. 
    Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA et al. 2010. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467:7314430–35
    [Google Scholar]
  60. 60. 
    Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J 2011. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470:7333279–85
    [Google Scholar]
  61. 61. 
    Melgar MF, Collins FS, Sethupathy P 2011. Discovery of active enhancers through bidirectional expression of short transcripts. Genome Biol 12:11R113
    [Google Scholar]
  62. 62. 
    Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW et al. 2010. Histone H3K27ac separates active from poised enhancers and predicts developmental state. PNAS 107:5021931–36
    [Google Scholar]
  63. 63. 
    Pekowska A, Benoukraf T, Zacarias-Cabeza J, Belhocine M, Koch F et al. 2011. H3K4 tri-methylation provides an epigenetic signature of active enhancers. EMBO J 30:204198–210
    [Google Scholar]
  64. 64. 
    Core LJ, Martins AL, Danko CG, Waters CT, Siepel A, Lis JT 2014. Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nat. Genet. 46:121311–20
    [Google Scholar]
  65. 65. 
    Henriques T, Scruggs BS, Inouye MO, Muse GW, Williams LH et al. 2018. Widespread transcriptional pausing and elongation control at enhancers. Genes Dev 32:126–41
    [Google Scholar]
  66. 66. 
    Haberle V, Arnold CD, Pagani M, Rath M, Schernhuber K, Stark A 2019. Transcriptional cofactors display specificity for distinct types of core promoters. Nature 570:7759122–26
    [Google Scholar]
  67. 67. 
    Ostuni R, Piccolo V, Barozzi I, Polletti S, Termanini A et al. 2013. Latent enhancers activated by stimulation in differentiated cells. Cell 152:1–2157–71
    [Google Scholar]
  68. 68. 
    Jadhav U, Cavazza A, Banerjee KK, Xie H, O'Neill NK et al. 2019. Extensive recovery of embryonic enhancer and gene memory stored in hypomethylated enhancer DNA. Mol. Cell 74:3542–54
    [Google Scholar]
  69. 69. 
    Ernst J, Kellis M. 2017. Chromatin-state discovery and genome annotation with ChromHMM. Nat. Protoc. 12:122478–92
    [Google Scholar]
  70. 70. 
    Whalen S, Truty RM, Pollard KS 2016. Enhancer-promoter interactions are encoded by complex genomic signatures on looping chromatin. Nat. Genet. 48:5488–96
    [Google Scholar]
  71. 71. 
    Fulco CP, Nasser J, Jones TR, Munson G, Bergman DT et al. 2019. Activity-by-contact model of enhancer specificity from thousands of CRISPR perturbations. bioRxiv 529990. https://doi.org/10.1101/529990
    [Crossref]
  72. 72. 
    Schoenfelder S, Fraser P. 2019. Long-range enhancer-promoter contacts in gene expression control. Nat. Rev. Genet. 20:8437–55
    [Google Scholar]
  73. 73. 
    Hill AJ, McFaline-Figueroa JL, Starita LM, Gasperini MJ, Matreyek KA et al. 2018. On the design of CRISPR-based single-cell molecular screens. Nat. Methods 15:4271–74
    [Google Scholar]
  74. 74. 
    Xie S, Cooley A, Armendariz D, Zhou P, Hon GC 2018. Frequent sgRNA-barcode recombination in single-cell perturbation assays. PLOS ONE 13:6e0198635
    [Google Scholar]
  75. 75. 
    Phillips JE, Corces VG. 2009. CTCF: master weaver of the genome. Cell 137:71194–211
    [Google Scholar]
  76. 76. 
    Nora EP, Goloborodko A, Valton AL, Gibcus JH, Uebersohn A et al. 2017. Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization. Cell 169:5930–44
    [Google Scholar]
  77. 77. 
    Schwarzer W, Abdennur N, Goloborodko A, Pekowska A, Fudenberg G et al. 2017. Two independent modes of chromatin organization revealed by cohesin removal. Nature 551:767851–56
    [Google Scholar]
  78. 78. 
    Rao SSP, Huang SC St, Hilaire BG, Engreitz JM, Perez EM et al. 2017. Cohesin loss eliminates all loop domains. Cell 171:2305–20
    [Google Scholar]
  79. 79. 
    Sigova AA, Abraham BJ, Ji X, Molinie B, Hannett NM et al. 2015. Transcription factor trapping by RNA in gene regulatory elements. Science 350:6263978–91
    [Google Scholar]
  80. 80. 
    Weintraub AS, Li CH, Zamudio AV, Sigova AA, Hannett NM et al. 2017. YY1 is a structural regulator of enhancer-promoter loops. Cell 171:71573–88
    [Google Scholar]
  81. 81. 
    Tuan D, Kong S, Hu K 1992. Transcription of the hypersensitive site HS2 enhancer in erythroid cells. PNAS 89:2311219–23
    [Google Scholar]
  82. 82. 
    Ashe HL, Monks J, Wijgerde M, Fraser P, Proudfoot NJ 1997. Intergenic transcription and transinduction of the human β-globin locus. Genes Dev 11:192494–509
    [Google Scholar]
  83. 83. 
    Masternak K, Peyraud N, Krawczyk M, Barras E, Reith W 2003. Chromatin remodeling and extragenic transcription at the MHC class II locus control region. Nat. Immunol. 4:2132–37
    [Google Scholar]
  84. 84. 
    Rogan DF, Cousins DJ, Santangelo S, Ioannou PA, Antoniou M et al. 2004. Analysis of intergenic transcription in the human IL-4/IL-13 gene cluster. PNAS 101:82446–51
    [Google Scholar]
  85. 85. 
    Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR et al. 2006. Genome-wide analysis of estrogen receptor binding sites. Nat. Genet. 38:111289–97
    [Google Scholar]
  86. 86. 
    Hah N, Danko CG, Core L, Waterfall JJ, Siepel A et al. 2011. A rapid, extensive, and transient transcriptional response to estrogen signaling in breast cancer cells. Cell 145:4622–34
    [Google Scholar]
  87. 87. 
    Wang D, Garcia-Bassets I, Benner C, Li W, Su X et al. 2011. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474:7351390–97
    [Google Scholar]
  88. 88. 
    Koch F, Fenouil R, Gut M, Cauchy P, Albert TK et al. 2011. Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Nat. Struct. Mol. Biol. 18:8956–63
    [Google Scholar]
  89. 89. 
    Young RS, Kumar Y, Bickmore WA, Taylor MS 2017. Bidirectional transcription initiation marks accessible chromatin and is not specific to enhancers. Genome Biol 18:242
    [Google Scholar]
  90. 90. 
    Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J et al. 2014. An atlas of active enhancers across human cell types and tissues. Nature 507:7493455–61
    [Google Scholar]
  91. 91. 
    Core LJ, Waterfall JJ, Lis JT 2008. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322:59091845–48
    [Google Scholar]
  92. 92. 
    Kwak H, Fuda NJ, Core LJ, Lis JT 2013. Precise maps of RNA polymerase reveal how promoters direct initiation and pausing. Science 339:6122950–53
    [Google Scholar]
  93. 93. 
    Nechaev S, Fargo DC, dos Santos G, Liu L, Gao Y, Adelman K 2010. Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science 327:5963335–38
    [Google Scholar]
  94. 94. 
    Henriques T, Gilchrist DA, Nechaev S, Bern M, Muse GW et al. 2013. Stable pausing by RNA polymerase II provides an opportunity to target and integrate regulatory signals. Mol. Cell 52:4517–28
    [Google Scholar]
  95. 95. 
    Hah N, Murakami S, Nagari A, Danko CG, Kraus WL 2013. Enhancer transcripts mark active estrogen receptor binding sites. Genome Res 23:81210–23
    [Google Scholar]
  96. 96. 
    Danko CG, Hyland SL, Core LJ, Martins AL, Waters CT et al. 2015. Identification of active transcriptional regulatory elements from GRO-seq data. Nat. Methods 12:5433–38
    [Google Scholar]
  97. 97. 
    Mikhaylichenko O, Bondarenko V, Harnett D, Schor IE, Males M et al. 2018. The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription. Genes Dev 32:142–57
    [Google Scholar]
  98. 98. 
    Azofeifa JG, Allen MA, Hendrix JR, Read T, Rubin JD, Dowell RD 2018. Enhancer RNA profiling predicts transcription factor activity. Genome Res 28:3334–44
    [Google Scholar]
  99. 99. 
    Li W, Notani D, Rosenfeld MG 2016. Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat. Rev. Genet. 17:4207–23
    [Google Scholar]
  100. 100. 
    Kaikkonen MU, Adelman K. 2018. Emerging roles of non-coding RNA transcription. Trends Biochem. Sci. 43:9654–67
    [Google Scholar]
  101. 101. 
    Struhl K. 2007. Transcriptional noise and the fidelity of initiation by RNA polymerase II. Nat. Struct. Mol. Biol. 14:2103–5
    [Google Scholar]
  102. 102. 
    Lai WKM, Pugh BF. 2017. Genome-wide uniformity of human “open” pre-initiation complexes. Genome Res 27:115–26
    [Google Scholar]
  103. 103. 
    Flynn RA, Do BT, Rubin AJ, Calo E, Lee B et al. 2016. 7SK-BAF axis controls pervasive transcription at enhancers. Nat. Struct. Mol. Biol. 23:3231–38
    [Google Scholar]
  104. 104. 
    Ling J, Ainol L, Zhang L, Yu X, Pi W, Tuan D 2004. HS2 enhancer function is blocked by a transcriptional terminator inserted between the enhancer and the promoter. J. Biol. Chem. 279:4951704–13
    [Google Scholar]
  105. 105. 
    Ho Y, Elefant F, Liebhaber SA, Cooke NE 2006. Locus control region transcription plays an active role in long-range gene activation. Mol. Cell 23:4619
    [Google Scholar]
  106. 106. 
    Engreitz JM, Haines JE, Perez EM, Munson G, Chen J et al. 2016. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 539:7629452–55
    [Google Scholar]
  107. 107. 
    Yoo EJ, Cooke NE, Liebhaber SA 2012. An RNA-independent linkage of noncoding transcription to long-range enhancer function. Mol. Cell. Biol. 32:102020–29
    [Google Scholar]
  108. 108. 
    Workman JL. 2006. Nucleosome displacement in transcription. Genes Dev 20:152009–17
    [Google Scholar]
  109. 109. 
    Gilchrist DA, Dos Santos G, Fargo DC, Xie B, Gao Y et al. 2010. Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation. Cell 143:4540–51
    [Google Scholar]
  110. 110. 
    Louder RK, He Y, López-Blanco JR, Fang J, Chacón P, Nogales E 2016. Structure of promoter-bound TFIID and model of human pre-initiation complex assembly. Nature 531:7596604–9
    [Google Scholar]
  111. 111. 
    Hu D, Gao X, Morgan MA, Herz HM, Smith ER, Shilatifard A 2013. The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol. Cell. Biol. 33:234745–54
    [Google Scholar]
  112. 112. 
    Kaikkonen MU, Spann NJ, Heinz S, Romanoski CE, Allison KA et al. 2013. Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol. Cell 51:3310–25
    [Google Scholar]
  113. 113. 
    Dorighi KM, Swigut T, Henriques T, Bhanu NV, Scruggs BS et al. 2017. Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promoters independently of H3K4 monomethylation. Mol. Cell 66:4568–76
    [Google Scholar]
  114. 114. 
    Rickels R, Herz HM, Sze CC, Cao K, Morgan MA et al. 2017. Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability. Nat. Genet. 49:111647–53
    [Google Scholar]
  115. 115. 
    Bose DA, Donahue G, Reinberg D, Shiekhattar R, Bonasio R, Berger SL 2017. RNA binding to CBP stimulates histone acetylation and transcription. Cell 168:1–2135–49
    [Google Scholar]
  116. 116. 
    Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA et al. 2013. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 503:7476371–76
    [Google Scholar]
  117. 117. 
    Beltran M, Yates CM, Skalska L, Dawson M, Reis FP et al. 2016. The interaction of PRC2 with RNA or chromatin is mutually antagonistic. Genome Res 26:7896–907
    [Google Scholar]
  118. 118. 
    Yu JR, Lee CH, Oksuz O, Stafford JM, Reinberg D 2019. PRC2 is high maintenance. Genes Dev 33:15–16903–35
    [Google Scholar]
  119. 119. 
    Jermann P, Hoerner L, Burger L, Schubeler D 2014. Short sequences can efficiently recruit histone H3 lysine 27 trimethylation in the absence of enhancer activity and DNA methylation. PNAS 111:33E3415–21
    [Google Scholar]
  120. 120. 
    Riising EM, Comet I, Leblanc B, Wu X, Johansen JV, Helin K 2014. Gene silencing triggers Polycomb repressive complex 2 recruitment to CpG islands genome wide. Mol. Cell 55:3347–60
    [Google Scholar]
  121. 121. 
    Lenhard B, Sandelin A, Carninci P 2012. Metazoan promoters: emerging characteristics and insights into transcriptional regulation. Nat. Rev. Genet. 13:4233–45
    [Google Scholar]
  122. 122. 
    Vo Ngoc L, Kassavetis GA, Kadonaga JT 2019. The RNA polymerase II core promoter in Drosophila. Genetics 212:113–24
    [Google Scholar]
  123. 123. 
    Nitta KR, Jolma A, Yin Y, Morgunova E, Kivioja T et al. 2015. Conservation of transcription factor binding specificities across 600 million years of bilateria evolution. eLife 4:e04837
    [Google Scholar]
  124. 124. 
    Mattioli K, Volders PJ, Gerhardinger C, Lee JC, Maass PG et al. 2019. High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity. Genome Res 29:3344–55
    [Google Scholar]
  125. 125. 
    Scruggs BS, Gilchrist DA, Nechaev S, Muse GW, Burkholder A et al. 2015. Bidirectional transcription arises from two distinct hubs of transcription factor binding and active chromatin. Mol. Cell 58:61101–12
    [Google Scholar]
  126. 126. 
    Andersson R, Sandelin A, Danko CG 2015. A unified architecture of transcriptional regulatory elements. Trends Genet 31:8426–33
    [Google Scholar]
  127. 127. 
    Crocker J, Abe N, Rinaldi L, McGregor AP, Frankel N et al. 2015. Low affinity binding site clusters confer Hox specificity and regulatory robustness. Cell 160:1–2191–203
    [Google Scholar]
  128. 128. 
    Farley EK, Olson KM, Zhang W, Brandt AJ, Rokhsar DS, Levine MS 2015. Suboptimization of developmental enhancers. Science 350:6258325–28
    [Google Scholar]
  129. 129. 
    Ramos AI, Barolo S. 2013. Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution. Philos. Trans. R. Soc. B 368:163220130018
    [Google Scholar]
  130. 130. 
    Rebeiz M, Tsiantis M. 2017. Enhancer evolution and the origins of morphological novelty. Curr. Opin. Genet. Dev. 45:115–23
    [Google Scholar]
  131. 131. 
    Nguyen TA, Jones RD, Snavely AR, Pfenning AR, Kirchner R et al. 2016. High-throughput functional comparison of promoter and enhancer activities. Genome Res 26:81023–33
    [Google Scholar]
  132. 132. 
    Dao LTM, Galindo-Albarrán AO, Castro-Mondragon JA, Andrieu-Soler C, Medina-Rivera A et al. 2017. Genome-wide characterization of mammalian promoters with distal enhancer functions. Nat. Genet. 49:71073–81
    [Google Scholar]
  133. 133. 
    Li G, Ruan X, Auerbach RK, Sandhu KS, Zheng M et al. 2012. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148:1–284–98
    [Google Scholar]
  134. 134. 
    Rennie S, Dalby M, Lloret-Llinares M, Bakoulis S, Dalager Vaagensø C et al. 2018. Transcription start site analysis reveals widespread divergent transcription in D. melanogaster and core promoter-encoded enhancer activities. Nucleic Acids Res 46:115455–69
    [Google Scholar]
  135. 135. 
    Andrey G, Mundlos S. 2017. The three-dimensional genome: regulating gene expression during pluripotency and development. Development 144:203646–58
    [Google Scholar]
  136. 136. 
    Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T et al. 2009. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326:5950289–93
    [Google Scholar]
  137. 137. 
    Dixon JR, Selvaraj S, Yue F, Kim A, Li Y et al. 2012. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:7398376–80
    [Google Scholar]
  138. 138. 
    Symmons O, Pan L, Remeseiro S, Aktas T, Klein F et al. 2016. The Shh topological domain facilitates the action of remote enhancers by reducing the effects of genomic distances. Dev. Cell 39:5529–43
    [Google Scholar]
  139. 139. 
    Lupiáñez DG, Kraft K, Heinrich V, Krawitz P, Brancati F et al. 2015. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161:51012–25
    [Google Scholar]
  140. 140. 
    Despang A, Schöpflin R, Franke M, Ali S, Jerkovic I et al. 2019. Functional dissection of TADs reveals non-essential and instructive roles in regulating gene expression. bioRxiv 566562. https://doi.org/10.1101/566562
    [Crossref]
  141. 141. 
    Williamson I, Kane L, Devenney PS, Flyamer IM, Anderson E et al. 2019. Developmentally regulated Shh expression is robust to TAD perturbations. Development 146:19dev179523
    [Google Scholar]
  142. 142. 
    Cuartero S, Weiss FD, Dharmalingam G, Guo Y, Ing-Simmons E et al. 2018. Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation. Nat. Immunol. 19:9932–41
    [Google Scholar]
  143. 143. 
    Pękowska A, Klaus B, Xiang W, Severino J, Daigle N et al. 2018. Gain of CTCF-anchored chromatin loops marks the exit from naive pluripotency. Cell Syst 7:5482–95
    [Google Scholar]
  144. 144. 
    Stadhouders R, Vidal E, Serra F, Di Stefano B, Le Dily F et al. 2018. Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming. Nat. Genet. 50:2238–49
    [Google Scholar]
  145. 145. 
    Krietenstein N, Abraham S, Venev SV, Abdennur N, Gibcus J et al. 2019. Ultrastructural details of mammalian chromosome architecture. bioRxiv 689922. https://doi.org/10.1101/639922
    [Crossref]
  146. 146. 
    Hsieh THS, Slobodyanyuk E, Hansen AS, Cattoglio C, Rando OJ et al. 2019. Resolving the 3D landscape of transcription-linked mammalian chromatin folding. bioRxiv 638775. https://doi.org/10.1101/638775
    [Crossref]
  147. 147. 
    Stevens TJ, Lando D, Basu S, Atkinson LP, Cao Y et al. 2017. 3D structures of individual mammalian genomes studied by single-cell Hi-C. Nature 544:764859–64
    [Google Scholar]
  148. 148. 
    Flyamer IM, Gassler J, Imakaev M, Brandão HB, Ulianov SV et al. 2017. Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. Nature 544:7648110–14
    [Google Scholar]
  149. 149. 
    Bintu B, Mateo LJ, Su JH, Sinnott-Armstrong NA, Parker M et al. 2018. Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells. Science 362:6413eaau1783
    [Google Scholar]
  150. 150. 
    Tan L, Xing D, Chang CH, Li H, Xie XS 2018. Three-dimensional genome structures of single diploid human cells. Science 361:6405924–28
    [Google Scholar]
  151. 151. 
    Gu B, Swigut T, Spencley A, Bauer MR, Chung M et al. 2018. Transcription-coupled changes in nuclear mobility of mammalian cis-regulatory elements. Science 359:63791050–55
    [Google Scholar]
  152. 152. 
    Cho WK, Jayanth N, English BP, Inoue T, Andrews JO et al. 2016. RNA polymerase II cluster dynamics predict mRNA output in living cells. eLife 5:e13617
    [Google Scholar]
  153. 153. 
    Fukaya T, Lim B, Levine M 2016. Enhancer control of transcriptional bursting. Cell 166:2358–68
    [Google Scholar]
  154. 154. 
    Larsson AJM, Johnsson P, Hagemann-Jensen M, Hartmanis L, Faridani OR et al. 2019. Genomic encoding of transcriptional burst kinetics. Nature 565:7738251–54
    [Google Scholar]
  155. 155. 
    Chen H, Levo M, Barinov L, Fujioka M, Jaynes JB, Gregor T 2018. Dynamic interplay between enhancer-promoter topology and gene activity. Nat. Genet. 50:91296–303
    [Google Scholar]
  156. 156. 
    Cho WK, Spille JH, Hecht M, Lee C, Li C et al. 2018. Mediator and RNA polymerase II clusters associate in transcription-dependent condensates. Science 361:6400412–15
    [Google Scholar]
  157. 157. 
    Benabdallah NS, Williamson I, Illingworth RS, Boyle S, Grimes GR et al. 2017. PARP mediated chromatin unfolding is coupled to long-range enhancer activation. bioRxiv 155325. https://doi.org/10.1101/155325
    [Crossref]
  158. 158. 
    Hnisz D, Shrinivas K, Young RA, Chakraborty AK, Sharp PA 2017. A phase separation model for transcriptional control. Cell 169:113–23
    [Google Scholar]
  159. 159. 
    Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB et al. 2010. Selective inhibition of BET bromodomains. Nature 468:73271067–73
    [Google Scholar]
  160. 160. 
    Lasko LM, Jakob CG, Edalji RP, Qiu W, Montgomery D et al. 2017. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature 550:7674128–32
    [Google Scholar]
  161. 161. 
    Holland AJ, Fachinetti D, Han JS, Cleveland DW 2012. Inducible, reversible system for the rapid and complete degradation of proteins in mammalian cells. PNAS 109:49E3350–57
    [Google Scholar]
  162. 162. 
    Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL et al. 2015. HaloPROTACS: use of small molecule PROTACs to induce degradation of HaloTag fusion proteins. ACS Chem. Biol. 10:81831–37
    [Google Scholar]
  163. 163. 
    Chung HK, Jacobs CL, Huo Y, Yang J, Krumm SA et al. 2015. Tunable and reversible drug control of protein production via a self-excising degron. Nat. Chem. Biol. 11:9713–20
    [Google Scholar]
/content/journals/10.1146/annurev-biochem-011420-095916
Loading
/content/journals/10.1146/annurev-biochem-011420-095916
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error