Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans

Key Points

  • Pausing is now recognized to be a pervasive feature of promoters in mammals and Drosophila melanogaster, and the evidence supporting this from genome-wide studies is presented.

  • The nomenclature of different promoter-associated RNA polymerase II (Pol II) species is explicitly defined in an effort to provide consistency in future literature.

  • The known mechanistic features of Pol II pausing and its release to productive elongation are described. Most genes are associated with factors that establish and release paused Pol II and therefore appear to progress through this step, although only a subset of genes appears to be directly regulated by pausing.

  • Multiple lines of evidence support the idea that Pol II and nucleosomes compete for promoter binding and suggest that a crucial role of paused Pol II involves maintenance of accessible promoter chromatin architecture.

  • Although pausing has been connected to extremely rapid and synchronous activation of genes, pausing is also highly associated with constitutively expressed genes that encode signalling and transcription factors. Pausing provides a mechanism to tune these key genes to cellular and external regulatory cues.

  • Pausing provides a point of regulation that is distinct from Pol II recruitment and initiation, and this may facilitate the integration of multiple cellular signals. Distinct signals that act through diverse targeted transcription factors can regulate different steps in the transcription pathway and provide a highly modulated transcriptional response at individual genes.

  • Pol II pausing and release occur at a point when 5′ end RNA processing and phosphorylation of the Pol II carboxy-terminal domain occurs. We speculate that by coupling RNA processing to the status and activity of Pol II itself, the cell ensures that nascent RNA is properly protected from degradation and efficiently matures into a functional mRNA.

Abstract

Recent years have witnessed a sea change in our understanding of transcription regulation: whereas traditional models focused solely on the events that brought RNA polymerase II (Pol II) to a gene promoter to initiate RNA synthesis, emerging evidence points to the pausing of Pol II during early elongation as a widespread regulatory mechanism in higher eukaryotes. Current data indicate that pausing is particularly enriched at genes in signal-responsive pathways. Here the evidence for pausing of Pol II from recent high-throughput studies will be discussed, as well as the potential interconnected functions of promoter-proximally paused Pol II.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Defining the terms used to describe promoter-associated Pol II complexes.
Figure 2: Patterns of Pol II distribution across gene regions.
Figure 3: Establishment and release of paused Pol II.
Figure 4: Illustrations of the main hypotheses for the functions of Pol II pausing.

Similar content being viewed by others

References

  1. Lis, J. Promoter-associated pausing in promoter architecture and postinitiation transcriptional regulation. Cold Spring Harb. Symp. Quant. Biol. 63, 347–356 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008). GRO-seq maps the position, amount and orientation of transcriptionally engaged RNA polymerases genome-wide and shows peaks of promoter-proximal polymerase residing on ~30% of human genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gilchrist, D. A. et al. Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation. Cell 143, 540–551 (2010). Global analyses of Pol II pausing and nucleosome occupancy reveal that Pol II and nucleosomes compete for promoter occupancy to regulate gene expression coordinately.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lee, C. et al. NELF and GAGA factor are linked to promoter-proximal pausing at many genes in Drosophila. Mol. Cell. Biol. 28, 3290–3300 (2008). Comprehensive analysis of promoter-associated Pol II in D. melanogaster using ChIP–chip and permanganate footprinting demonstrates that NELF-mediated pausing of Pol II is common in D. melanogaster.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Min, I. M. et al. Regulating RNA polymerase pausing and transcription elongation in embryonic stem cells. Genes Dev. 25, 742–754 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Muse, G. W. et al. RNA polymerase is poised for activation across the genome. Nature Genet. 39, 1507–1511 (2007). Genome-wide Pol II ChIP–chip assays, coupled with permanganate footprinting and genetic manipulation of NELF, indicated that Pol II pausing is widespread in D. melanogaster.

    Article  CAS  PubMed  Google Scholar 

  7. Nechaev, S. et al. Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science 327, 335–338 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Rahl, P. B. et al. c-Myc tegulates transcriptional pause release. Cell 141, 432–445 (2010). Investigation of transcription factor MYC reveals its important role in releasing paused Pol II through recruitment of P-TEFb.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nature Genet. 39, 1512–1516 (2007). Genome-wide Pol II ChIP–chip assays indicated that Pol II pausing is widespread during early embryonic development in D. melanogaster.

    Article  CAS  PubMed  Google Scholar 

  10. Fraser, N. W., Sehgal, P. B. & Darnell, J. E. DRB-induced premature termination of late adenovirus transcription. Nature 272, 590–593 (1978).

    Article  CAS  PubMed  Google Scholar 

  11. Gariglio, P., Bellard, M. & Chambon, P. Clustering of RNA polymerase B molecules in the 5′ moiety of the adult beta-globin gene of hen erythrocytes. Nucleic Acids Res. 9, 2589–2598 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gilmour, D. S. & Lis, J. T. RNA polymerase II interacts with the promoter region of the noninduced hsp70 gene in Drosophila melanogaster cells. Mol. Cell. Biol. 6, 3984–3989 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rougvie, A. E. & Lis, J. T. The RNA polymerase II molecule at the 5′ end of the uninduced hsp70 gene of D. melanogaster is transcriptionally engaged. Cell 54, 795–804 (1988). Nuclear run-on assays demonstrate that the Pol II complex associated with the Hsp70 promoter is transcriptionally engaged but is unable to penetrate further into the gene without heat shock induction.

    Article  CAS  PubMed  Google Scholar 

  14. Giardina, C., Perez-Riba, M. & Lis, J. T. Promoter melting and TFIID complexes on Drosophila genes in vivo. Genes Dev. 6, 2190–2200 (1992).

    Article  CAS  PubMed  Google Scholar 

  15. Rasmussen, E. B. & Lis, J. T. In vivo transcriptional pausing and cap formation on three Drosophila heat shock genes. Proc. Natl Acad. Sci. USA 90, 7923–7927 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Grayhack, E. J., Yang, X. J., Lau, L. F. & Roberts, J. W. Phage lambda gene Q antiterminator recognizes RNA polymerase near the promoter and accelerates it through a pause site. Cell 42, 259–269 (1985).

    Article  CAS  PubMed  Google Scholar 

  17. Rougvie, A. E. & Lis, J. T. Postinitiation transcriptional control in Drosophila melanogaster. Mol. Cell. Biol. 10, 6041–6045 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Law, A., Hirayoshi, K., O'Brien, T. & Lis, J. T. Direct cloning of DNA that interacts in vivo with a specific protein: application to RNA polymerase II and sites of pausing in Drosophila. Nucleic Acids Res. 26, 919–924 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Strobl, L. J. & Eick, D. Hold back of RNA polymerase II at the transcription start site mediates down-regulation of c-Myc in vivo. EMBO J. 11, 3307–3314 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Krumm, A., Meulia, T., Brunvand, M. & Groudine, M. The block to transcriptional elongation within the human c-myc gene is determined in the promoter-proximal region. Genes Dev. 6, 2201–2213 (1992).

  21. Plet, A., Eick, D. & Blanchard, J. M. Elongation and premature termination of transcripts initiated from c-Fos and c-Myc promoters show dissimilar patterns. Oncogene 10, 319–328 (1995).

    CAS  PubMed  Google Scholar 

  22. Kao, S. Y., Calman, A. F., Luciw, P. A. & Peterlin, B. M. Anti-termination of transcription within the long terminal repeat of HIV-1 by Tat gene product. Nature 330, 489–493 (1987).

    Article  CAS  PubMed  Google Scholar 

  23. Stargell, L. A. & Struhl, K. Mechanisms of transcriptional activation in vivo: two steps forward. Trends Genet. 12, 311–315 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Ptashne, M. & Gann, A. Transcriptional activation by recruitment. Nature 386, 569–577 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Steinmetz, E. J. et al. Genome-wide distribution of yeast RNA polymerase II and its control by Sen1 helicase. Mol. Cell 24, 735–746 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Kim, T. H. et al. A high-resolution map of active promoters in the human genome. Nature 436, 876–880 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Larschan, E. et al. X chromosome dosage compensation via enhanced transcriptional elongation in Drosophila. Nature 471, 115–118 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kephart, D. D., Marshall, N. F. & Price, D. H. Stability of Drosophila RNA polymerase II elongation complexes in vitro. Mol. Cell. Biol. 12, 2067–2077 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nechaev, S. & Adelman, K. Promoter-proximal Pol II: when stalling speeds things up. Cell Cycle 7, 1539–1544 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Hargreaves, D. C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schones, D. E. et al. Dynamic regulation of nucleosome positioning in the human genome. Cell 132, 887–898 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Peterlin, B. M. & Price, D. H. Controlling the elongation phase of transcription with P-TEFb. Mol. Cell 23, 297–305 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Gromak, N., West, S. & Proudfoot, N. J. Pause sites promote transcriptional termination of mammalian RNA polymerase II. Mol. Cell. Biol. 26, 3986–3996 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Proudfoot, N. J. Ending the message: poly(A) signals then and now. Genes Dev. 25, 1770–1782 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Carrillo Oesterreich, F., Preibisch, S. & Neugebauer, K. M. Global analysis of nascent RNA reveals transcriptional pausing in terminal exons. Mol. Cell 40, 571–581 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. de la Mata, M. et al. A slow RNA polymerase II affects alternative splicing in vivo. Mol. Cell 12, 525–532 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Juven-Gershon, T. & Kadonaga, J. T. Regulation of gene expression via the core promoter and the basal transcriptional machinery. Dev. Biol. 339, 225–229 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Roeder, R. G. Transcriptional regulation and the role of diverse coactivators in animal cells. FEBS Lett. 579, 909–915 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Marshall, N. F. & Price, D. H. Control of formation of two distinct classes of RNA polymerase II elongation complexes. Mol. Cell. Biol. 12, 2078–2090 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wada, T. et al. DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev. 12, 343–356 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yamaguchi, Y. et al. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 97, 41–51 (1999). Biochemical assays reveal the presence and identity of the NELF complex and elucidate its role in inhibiting early transcription elongation.

    Article  CAS  PubMed  Google Scholar 

  43. Narita, T. et al. Human transcription elongation factor NELF: identification of novel subunits and reconstitution of the functionally active complex. Mol. Cell. Biol. 23, 1863–1873 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cheng, B. et al. Functional association of Gdown1 with RNA polymerase II poised on human genes. Mol. Cell 45, 38–50 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Brannan, K. et al. mRNA decapping factors and the exonuclease Xrn2 function in widespread premature termination of RNA polymerase II transcription. Mol. Cell 46, 311–324 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Marshall, N. F. & Price, D. H. Purification of P-TEFb, a transcription factor required for the transition into productive elongation. J. Biol. Chem. 270, 12335–12338 (1995). This pioneering paper describes the purification and characterization of the kinase P-TEFb.

    Article  CAS  PubMed  Google Scholar 

  47. Wada, T., Takagi, T., Yamaguchi, Y., Watanabe, D. & Handa, H. Evidence that P-TEFb alleviates the negative effect of DSIF on RNA polymerase II-dependent transcription in vitro. EMBO J. 17, 7395–7403 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Czudnochowski, N., Bosken, C. A. & Geyer, M. Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition. Nature Commun. 3, 842 (2012).

    Article  CAS  Google Scholar 

  49. Jang, M. et al. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 19, 523–534 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Yang, Z. et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 19, 535–545 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Barboric, M., Nissen, R. M., Kanazawa, S., Jabrane-Ferrat, N. & Peterlin, B. M. NF-κB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol. Cell 8, 327–337 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Eberhardy, S. & Farnham, P. Myc recruits P-TEFb to mediate the final step in the transcriptional activation of the cad promoter. J. Biol. Chem. 277, 40156–40162 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Takahashi, H. et al. Human mediator subunit MED26 functions as a docking site for transcription elongation factors. Cell 146, 92–104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mueller, D. et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood 110, 4445–4454 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lin, C. et al. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol. Cell 37, 429–437 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sobhian, B. et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol. Cell 38, 439–451 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. He, N. et al. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol. Cell 38, 428–438 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ni, Z. et al. P-TEFb is critical for the maturation of RNA polymerase II into productive elongation in vivo. Mol. Cell. Biol. 28, 1161–1170 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Workman, J. L. Nucleosome displacement in transcription. Genes Dev. 20, 2009–2017 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Boeger, H., Griesenbeck, J., Strattan, J. S. & Kornberg, R. D. Nucleosomes unfold completely at a transcriptionally active promoter. Mol. Cell 11, 1587–1598 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Reinke, H. & Horz, W. Histones are first hyperacetylated and then lose contact with the activated PHO5 promoter. Mol. Cell 11, 1599–1607 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Wu, C. The 5′ ends of Drosophila heat shock genes in chromatin are hypersensitive to DNase I. Nature 286, 854–860 (1980).

    Article  CAS  PubMed  Google Scholar 

  63. Costlow, N. & Lis, J. T. High-resolution mapping of DNase I-hypersensitive sites of Drosophila heat shock genes in Drosophila melanogaster and Saccharomyces cerevisiae. Mol. Cell. Biol. 4, 1853–1863 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Shopland, L. S., Hirayoshi, K., Fernandes, M. & Lis, J. T. HSF access to heat shock elements in vivo depends critically on promoter architecture defined by GAGA factor, TFIID, and RNA polymerase II binding sites. Genes Dev. 9, 2756–2769 (1995).

    Article  CAS  PubMed  Google Scholar 

  65. Gilchrist, D. A. et al. NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly. Genes Dev. 22, 1921–1933 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Leibovitch, B. A. et al. GAGA factor and the TFIID complex collaborate in generating an open chromatin structure at the Drosophila melanogaster hsp26 promoter. Mol. Cell. Biol. 22, 6148–6157 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee, H., Kraus, K. W., Wolfner, M. F. & Lis, J. T. DNA sequence requirements for generating paused polymerase at the start of hsp70. Genes Dev. 6, 284–295 (1992).

    Article  CAS  PubMed  Google Scholar 

  68. Iyer, V. & Struhl, K. Poly(dA:dT), a ubiquitous promoter element that stimulates transcription via its intrinsic DNA structure. EMBO J. 14, 2570–2579 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kaplan, N. et al. The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458, 362–366 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature Rev. Genet. 13, 484–492 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Tillo, D. et al. High nucleosome occupancy is encoded at human regulatory sequences. PLoS ONE 5, e9129 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Valouev, A. et al. Determinants of nucleosome organization in primary human cells. Nature 474, 516–520 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gilchrist, D. A. & Adelman, K. Coupling polymerase pausing and chromatin landscapes for precise regulation of transcription. Biochim. Biophys. Acta 1819, 700–706 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chopra, V. S. et al. The polycomb group mutant esc leads to augmented levels of paused Pol II in the Drosophila embryo. Mol. Cell 42, 837–844 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Weake, V. & Workman, J. Inducible gene expression: diverse regulatory mechanisms. Nature Rev. Genet. 11, 426–437 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Bryant, G. O. & Ptashne, M. Independent recruitment in vivo by Gal4 of two complexes required for transcription. Mol. Cell 11, 1301–1309 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Yudkovsky, N., Ranish, J. A. & Hahn, S. A transcription reinitiation intermediate that is stabilized by activator. Nature 408, 225–229 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Bai, L., Charvin, G., Siggia, E. D. & Cross, F. R. Nucleosome-depleted regions in cell-cycle-regulated promoters ensure reliable gene expression in every cell cycle. Dev. Cell 18, 544–555 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hendrix, D. A., Hong, J. W., Zeitlinger, J., Rokhsar, D. S. & Levine, M. S. Promoter elements associated with RNA Pol II stalling in the Drosophila embryo. Proc. Natl Acad. Sci. USA 105, 7762–7767 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Boettiger, A. N. & Levine, M. Synchronous and stochastic patterns of gene activation in the Drosophila embryo. Science 325, 471–473 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Aida, M. et al. Transcriptional pausing caused by NELF plays a dual role in regulating immediate-early expression of the junB gene. Mol. Cell. Biol. 26, 6094–6104 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Adelman, K. et al. Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling. Proc. Natl Acad. Sci. USA 106, 18207–18212 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Nissen, R. M. & Yamamoto, K. R. The glucocorticoid receptor inhibits NFκB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev. 14, 2314–2329 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kininis, M. et al. Genomic analyses of transcription factor binding, histone acetylation, and gene expression reveal mechanistically distinct classes of estrogen-regulated promoters. Mol. Cell. Biol. 27, 5090–5104 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lin, C. et al. Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC). Genes Dev. 25, 1486–1498 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gilchrist, D. A. et al. Regulating the regulators: the pervasive effects of Pol II pausing on stimulus-responsive gene networks. Genes Dev. 26, 933–944 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Blau, J. et al. Three functional classes of transcriptional activation domain. Mol. Cell. Biol. 16, 2044–2055 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Egloff, S., Dienstbier, M. & Murphy, S. Updating the RNA polymerase CTD code: adding gene-specific layers. Trends Genet. 28, 333–341 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Ghosh, A., Shuman, S. & Lima, C. D. Structural insights to how mammalian capping enzyme reads the CTD code. Mol. Cell 43, 299–310 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Mandal, S. S. et al. Functional interactions of RNA-capping enzyme with factors that positively and negatively regulate promoter escape by RNA polymerase II. Proc. Natl Acad. Sci. USA 101, 7572–7577 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Moore, M. J. & Proudfoot, N. J. Pre-mRNA processing reaches back to transcription and ahead to translation. Cell 136, 688–700 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Buratowski, S. Progression through the RNA polymerase II CTD cycle. Mol. Cell 36, 541–546 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Levine, M. Paused, R. N. A. Polymerase II as a developmental checkpoint. Cell 145, 502–511 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gould, T. J., Verkhusha, V. V. & Hess, S. T. Imaging biological structures with fluorescence photoactivation localization microscopy. Nature Protoc. 4, 291–308 (2009).

    Article  CAS  Google Scholar 

  98. Rasmussen, E. B. & Lis, J. T. Short transcripts of the ternary complex provide insight into RNA polymerase II elongational pausing. J. Mol. Biol. 252, 522–535 (1995).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the members of the Lis and Adelman laboratories for their helpful discussions on this Review. Funding for this work was provided by US National Institutes of Health (NIH) grant GM25232 to J.L. and the Intramural Research Program of the NIH National Institute of Environmental Health Sciences (Z01 ES101987) to K.A.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Karen Adelman or John T. Lis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Karen Adelman's homepage

Nature Reviews Genetics Series on Modes of transcriptional regulation

Glossary

Pre-initiation complex

(PIC). An entry form of Pol II in a complex with general transcription factors in which the polymerase is bound to the promoter DNA but has not yet initiated RNA synthesis.

Heat shock genes

(Hsp genes). These genes are a set of highly conserved genes that encode molecular chaperones. These genes are rapidly induced in cells or organisms in response to various cellular stresses, including a several-degree increase in temperature.

Long terminal repeat

(LTR). In HIV, this promoter resides in a region of LTRs. Transcription from this promoter produces both viral proteins and new RNA genomes.

Ligation-meditated PCR

(LM-PCR). A technique that can be used to map the ends of DNA fragments precisely from a specific region of the genome. Small DNA linkers are added to ends of DNA samples and then primers that are complementary to this linker are combined with a sequence-specific primer to amplify the DNA of interest by PCR.

CpG islands

Regions of higher-than-normal CpG sequence content that are on average 1,000 base pairs in length. Such regions contain ~70% of all mammalian promoters, including both genes that are highly regulated and broadly expressed.

Polycomb

Regulate chromatin structure to contribute to epigenetic inheritance of a repressed state. They form several complexes, which are broadly defined as Polycomb repressive complexes 1 and 2 (PRC1 and PRC2), and these are thought to compact chromatin structure.

Bivalent genes

Exhibit histone modifications that are characteristic of both gene repression and activation. These genes display low levels of Pol II occupancy and activity and are hypothesized to be poised for activation during development.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Adelman, K., Lis, J. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat Rev Genet 13, 720–731 (2012). https://doi.org/10.1038/nrg3293

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg3293

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research