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.

Born to run: control of transcription elongation by RNA polymerase II

Subjects

Abstract

The dynamic regulation of transcription elongation by RNA polymerase II (Pol II) is an integral part of the implementation of gene expression programmes during development. In most metazoans, the majority of transcribed genes exhibit transient pausing of Pol II at promoter-proximal regions, and the release of Pol II into gene bodies is controlled by many regulatory factors that respond to environmental and developmental cues. Misregulation of the elongation stage of transcription is implicated in cancer and other human diseases, suggesting that mechanistic understanding of transcription elongation control is therapeutically relevant. In this Review, we discuss the features, establishment and maintenance of Pol II pausing, the transition into productive elongation, the control of transcription elongation by enhancers and by factors of other cellular processes, such as topoisomerases and poly(ADP-ribose) polymerases (PARPs), and the potential of therapeutic targeting of the elongation stage of transcription by Pol II.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Establishment, maintenance and release of RNA polymerase II pausing.
Fig. 2: Release of RNA polymerase II pausing by P-TEFb-containing complexes.
Fig. 3: Post-translational modification of RNA polymerase II and histones at active genes with pausing and at active enhancers.
Fig. 4: Regulation of transcription elongation by enhancers.
Fig. 5: Cancer addiction into transcription elongation.

References

  1. Muse, G. W. et al. RNA polymerase is poised for activation across the genome. Nat. Genet. 39, 1507–1511 (2007).

    PubMed  PubMed Central  Article  CAS  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). This study introduces the method of global nuclear run-on sequencing (GRO-seq) that allows sensitive detection of promoter-proximal pausing and enhancer RNAs.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  3. 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).

    PubMed  Article  CAS  Google Scholar 

  4. Peng, J., Marshall, N. F. & Price, D. H. Identification of a cyclin subunit required for the function of Drosophila P-TEFb. J. Biol. Chem. 273, 13855–13860 (1998).

    PubMed  Article  CAS  Google Scholar 

  5. Jonkers, I., Kwak, H. & Lis, J. T. Genome-wide dynamics of Pol II elongation and its interplay with promoter proximal pausing, chromatin, and exons. eLife 3, e02407 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. Luo, Z. et al. The super elongation complex family of RNA polymerase II elongation factors: gene target specificity and transcriptional output. Mol. Cell. Biol. 32, 2608–2617 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 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). This study identifies the SEC, which contains translocation partners of the MLL gene in leukaemia.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  9. Jang, M. K. 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).

    PubMed  Article  CAS  Google Scholar 

  10. Yang, Z., Zhu, Q., Luo, K. & Zhou, Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 414, 317–322 (2001).

    PubMed  Article  CAS  Google Scholar 

  11. Nguyen, V. T., Kiss, T., Michels, A. A. & Bensaude, O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 414, 322–325 (2001).

    PubMed  Article  CAS  Google Scholar 

  12. Herzel, L., Ottoz, D. S. M., Alpert, T. & Neugebauer, K. M. Splicing and transcription touch base: co-transcriptional spliceosome assembly and function. Nat. Rev. Mol. Cell Biol. 18, 637–650 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. Shilatifard, A., Conaway, R. C. & Conaway, J. W. The RNA polymerase II elongation complex. Annu. Rev. Biochem. 72, 693–715 (2003).

    PubMed  Article  CAS  Google Scholar 

  14. 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).

    PubMed  Article  CAS  Google Scholar 

  15. Shilatifard, A., Lane, W. S., Jackson, K. W., Conaway, R. C. & Conaway, J. W. An RNA polymerase II elongation factor encoded by the human ELL gene. Science 271, 1873–1876 (1996). This study implicates a bona fide transcriptional elongation factor as a driver of human cancer.

    PubMed  Article  CAS  Google Scholar 

  16. Hartzog, G. A., Wada, T., Handa, H. & Winston, F. Evidence that Spt4, Spt5, and Spt6 control transcription elongation by RNA polymerase II in Saccharomyces cerevisiae. Genes Dev. 12, 357–369 (1998).

    PubMed  Article  CAS  Google Scholar 

  17. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 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).

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nat. Genet. 39, 1512–1516 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Krumm, A., Hickey, L. B. & Groudine, M. Promoter-proximal pausing of RNA polymerase II defines a general rate-limiting step after transcription initiation. Genes Dev. 9, 559–572 (1995).

    PubMed  Article  CAS  Google Scholar 

  23. Rahl, P. B. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. Reppas, N. B., Wade, J. T., Church, G. M. & Struhl, K. The transition between transcriptional initiation and elongation in E. coli is highly variable and often rate limiting. Mol. Cell 24, 747–757 (2006).

    PubMed  Article  CAS  Google Scholar 

  25. Chen, F. X. et al. PAF1, a molecular regulator of promoter-proximal pausing by RNA polymerase II. Cell 162, 1003–1015 (2015). This study identifies PAF1 as a pausing factor that prevents the release of paused Pol II into productive elongation.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. Titov, D. V. et al. XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat. Chem. Biol. 7, 182–188 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. Chen, F., Gao, X. & Shilatifard, A. Stably paused genes revealed through inhibition of transcription initiation by the TFIIH inhibitor triptolide. Genes Dev. 29, 39–47 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. Henriques, T. et al. Stable pausing by RNA polymerase II provides an opportunity to target and integrate regulatory signals. Mol. Cell 52, 517–528 (2013).

    PubMed  Article  CAS  Google Scholar 

  29. Shao, W. & Zeitlinger, J. Paused RNA polymerase II inhibits new transcriptional initiation. Nat. Genet. 49, 1045–1051 (2017). References 27–29 reveal the existence of genes with stably paused Pol II.

    PubMed  Article  CAS  Google Scholar 

  30. Nilson, K. A. et al. Oxidative stress rapidly stabilizes promoter-proximal paused Pol II across the human genome. Nucleic Acids Res. 45, 11088–11105 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. Day, D. S. et al. Comprehensive analysis of promoter-proximal RNA polymerase II pausing across mammalian cell types. Genome Biol. 17, 120 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. Krebs, A. R. et al. Genome-wide single-molecule footprinting reveals high RNA polymerase II turnover at paused promoters. Mol. Cell 67, 411–422.e4 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. Lagha, M. et al. Paused Pol II coordinates tissue morphogenesis in the Drosophila embryo. Cell 153, 976–987 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  35. Li, J. & Gilmour, D. S. Distinct mechanisms of transcriptional pausing orchestrated by GAGA factor and M1BP, a novel transcription factor. EMBO J. 32, 1829–1841 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. Ginno, P. A., Lim, Y. W., Lott, P. L., Korf, I. & Chedin, F. GC skew at the 5′ and 3′ ends of human genes links R-loop formation to epigenetic regulation and transcription termination. Genome Res. 23, 1590–1600 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. Sanz, L. A. et al. Prevalent, dynamic, and conserved R-Loop structures associate with specific epigenomic signatures in mammals. Mol. Cell 63, 167–178 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. Lesnik, E. A. & Freier, S. M. Relative thermodynamic stability of DNA, RNA, and DNA:RNA hybrid duplexes: relationship with base composition and structure. Biochemistry 34, 10807–10815 (1995).

    PubMed  Article  CAS  Google Scholar 

  39. Tous, C. & Aguilera, A. Impairment of transcription elongation by R-loops in vitro. Biochem. Biophys. Res. Commun. 360, 428–432 (2007).

    PubMed  Article  CAS  Google Scholar 

  40. Belotserkovskii, B. P., Soo Shin, J. H. & Hanawalt, P. C. Strong transcription blockage mediated by R-loop formation within a G-rich homopurine-homopyrimidine sequence localized in the vicinity of the promoter. Nucleic Acids Res. 45, 6589–6599 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. Ratmeyer, L., Vinayak, R., Zhong, Y. Y., Zon, G. & Wilson, W. D. Sequence specific thermodynamic and structural properties for DNA. RNA duplexes. Biochemistry 33, 5298–5304 (1994).

    PubMed  Article  CAS  Google Scholar 

  42. Kellner, W. A., Bell, J. S. & Vertino, P. M. GC skew defines distinct RNA polymerase pause sites in CpG island promoters. Genome Res. 25, 1600–1609 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. Ginno, P. A., Lott, P. L., Christensen, H. C., Korf, I. & Chedin, F. R-Loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Mol. Cell 45, 814–825 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. Lam, E. Y., Beraldi, D., Tannahill, D. & Balasubramanian, S. G-Quadruplex structures are stable and detectable in human genomic DNA. Nat. Commun. 4, 1796 (2013).

    PubMed  Article  CAS  Google Scholar 

  45. Shrestha, P., Xiao, S., Dhakal, S., Tan, Z. & Mao, H. Nascent RNA transcripts facilitate the formation of G-quadruplexes. Nucleic Acids Res. 42, 7236–7246 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. Eddy, J. et al. G4 motifs correlate with promoter-proximal transcriptional pausing in human genes. Nucleic Acids Res. 39, 4975–4983 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. Kwak, H., Fuda, N. J., Core, L. J. & Lis, J. T. Precise maps of RNA polymerase reveal how promoters direct initiation and pausing. Science 339, 950–953 (2013). This study introduces precision run-on and Ssquencing (PRO-seq), which allows the mapping of engaged Pol II at base-pair resolution.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  49. Mavrich, T. N. et al. Nucleosome organization in the Drosophila genome. Nature 453, 358–362 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. Ozsolak, F., Song, J. S., Liu, X. S. & Fisher, D. E. High-throughput mapping of the chromatin structure of human promoters. Nat. Biotechnol. 25, 244–248 (2007).

    PubMed  Article  CAS  Google Scholar 

  51. Yuan, G. C. et al. Genome-scale identification of nucleosome positions in S. cerevisiae. Science 309, 626–630 (2005).

    PubMed  Article  CAS  Google Scholar 

  52. Booth, G. T., Wang, I. X., Cheung, V. G. & Lis, J. T. Divergence of a conserved elongation factor and transcription regulation in budding and fission yeast. Genome Res. 26, 799–811 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 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).

    PubMed  Article  CAS  Google Scholar 

  54. Lee, C. K., Shibata, Y., Rao, B., Strahl, B. D. & Lieb, J. D. Evidence for nucleosome depletion at active regulatory regions genome-wide. Nat. Genet. 36, 900–905 (2004).

    PubMed  Article  CAS  Google Scholar 

  55. Tillo, D. & Hughes, T. R. G+C content dominates intrinsic nucleosome occupancy. BMC Bioinformatics 10, 442 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 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). This work reports that paused Pol II competes with nucleosomes for occupancy at paused promoters.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. Fenouil, R. et al. CpG islands and GC content dictate nucleosome depletion in a transcription-independent manner at mammalian promoters. Genome Res. 22, 2399–2408 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. de Dieuleveult, M. et al. Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells. Nature 530, 113–116 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. Kubik, S. et al. Nucleosome stability distinguishes two different promoter types at all protein-coding genes in yeast. Mol. Cell 60, 422–434 (2015).

    PubMed  Article  CAS  Google Scholar 

  61. Vera, D. L. et al. Differential nuclease sensitivity profiling of chromatin reveals biochemical footprints coupled to gene expression and functional DNA elements in maize. Plant Cell 26, 3883–3893 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. Henikoff, S., Henikoff, J. G., Sakai, A., Loeb, G. B. & Ahmad, K. Genome-wide profiling of salt fractions maps physical properties of chromatin. Genome Res. 19, 460–469 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. Jin, C. et al. H3.3/H2A. Z double variant-containing nucleosomes mark ‘nucleosome-free regions’ of active promoters and other regulatory regions. Nat. Genet. 41, 941–945 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. Ishii, H., Kadonaga, J. T. & Ren, B. MPE-seq, a new method for the genome-wide analysis of chromatin structure. Proc. Natl Acad. Sci. USA 112, E3457–E3465 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. Mieczkowski, J. et al. MNase titration reveals differences between nucleosome occupancy and chromatin accessibility. Nat. Commun. 7, 11485 (2016). This study introduces a MNase titration-based methodology to measure chromatin accessibility.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. Xi, Y., Yao, J., Chen, R., Li, W. & He, X. Nucleosome fragility reveals novel functional states of chromatin and poises genes for activation. Genome Res. 21, 718–724 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. Chereji, R. V., Ocampo, J. & Clark, D. J. MNase-sensitive complexes in yeast: nucleosomes and non-histone barriers. Mol. Cell 65, 565–577.e3 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. Kubik, S. et al. A reply to “MNase-sensitive complexes in yeast: nucleosomes and non-histone barriers,” by Chereji et al. Mol. Cell 65, 578–580 (2017).

    PubMed  Article  CAS  Google Scholar 

  69. Voong, L. N. et al. Insights into nucleosome organization in mouse embryonic stem cells through chemical mapping. Cell 167, 1555–1570 (2016). This study uses a chemical mapping approach to evaluate pausing and nucleosome occupancy at promoter regions.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. Weber, C. M., Ramachandran, S. & Henikoff, S. Nucleosomes are context-specific, H2A. Z-modulated barriers to RNA polymerase. Mol. Cell 53, 819–830 (2014).

    PubMed  Article  CAS  Google Scholar 

  71. Hu, G. et al. H2A. Z facilitates access of active and repressive complexes to chromatin in embryonic stem cell self-renewal and differentiation. Cell Stem Cell 12, 180–192 (2013).

    PubMed  Article  CAS  Google Scholar 

  72. Sainsbury, S., Bernecky, C. & Cramer, P. Structural basis of transcription initiation by RNA polymerase II. Nat. Rev. Mol. Cell Biol. 16, 129–143 (2015).

    PubMed  Article  CAS  Google Scholar 

  73. Grunberg, S. & Hahn, S. Structural insights into transcription initiation by RNA polymerase II. Trends Biochem. Sci. 38, 603–611 (2013).

    PubMed  Article  CAS  Google Scholar 

  74. Compe, E. & Egly, J. M. TFIIH: when transcription met DNA repair. Nat. Rev. Mol. Cell Biol. 13, 343–354 (2012).

    PubMed  Article  CAS  Google Scholar 

  75. Kim, T. K., Ebright, R. H. & Reinberg, D. Mechanism of ATP-dependent promoter melting by transcription factor IIH. Science 288, 1418–1422 (2000).

    PubMed  Article  CAS  Google Scholar 

  76. Li, J. et al. Kinetic competition between elongation rate and binding of NELF controls promoter-proximal pausing. Mol. Cell 50, 711–722 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. Glover-Cutter, K. et al. TFIIH-associated Cdk7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II. Mol. Cell. Biol. 29, 5455–5464 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. Akhtar, M. S. et al. TFIIH kinase places bivalent marks on the carboxy-terminal domain of RNA polymerase II. Mol. Cell 34, 387–393 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. Harlen, K. M. & Churchman, L. S. The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain. Nat. Rev. Mol. Cell Biol. 18, 263–273 (2017).

    PubMed  Article  CAS  Google Scholar 

  80. Allen, B. L. & Taatjes, D. J. The mediator complex: a central integrator of transcription. Nat. Rev. Mol. Cell Biol. 16, 155–166 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. Soutourina, J. Transcription regulation by the mediator complex. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/nrm.2017.115 (2017).

  82. Jeronimo, C. & Robert, F. Kin28 regulates the transient association of mediator with core promoters. Nat. Struct. Mol. Biol. 21, 449–455 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. Bentley, D. L. Coupling mRNA processing with transcription in time and space. Nat. Rev. Genet. 15, 163–175 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. Nilson, K. A. et al. THZ1 reveals roles for Cdk7 in co-transcriptional capping and pausing. Mol. Cell 59, 576–587 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. Ebmeier, C. C. et al. Human TFIIH kinase CDK7 regulates transcription-associated chromatin modifications. Cell Rep. 20, 1173–1186 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. Larochelle, S. et al. Cyclin-dependent kinase control of the initiation-to-elongation switch of RNA polymerase II. Nat. Struct. Mol. Biol. 19, 1108–1115 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. Yamaguchi, Y. et al. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 97, 41–51 (1999).

    PubMed  Article  CAS  Google Scholar 

  89. Renner, D. B., Yamaguchi, Y., Wada, T., Handa, H. & Price, D. H. A highly purified RNA polymerase II elongation control system. J. Biol. Chem. 276, 42601–42609 (2001).

    PubMed  Article  CAS  Google Scholar 

  90. Palangat, M., Renner, D. B., Price, D. H. & Landick, R. A negative elongation factor for human RNA polymerase II inhibits the anti-arrest transcript-cleavage factor TFIIS. Proc. Natl Acad. Sci. USA 102, 15036–15041 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. Wen, Y. & Shatkin, A. J. Transcription elongation factor hSPT5 stimulates mRNA capping. Genes Dev. 13, 1774–1779 (1999).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. Doamekpor, S. K., Sanchez, A. M., Schwer, B., Shuman, S. & Lima, C. D. How an mRNA capping enzyme reads distinct RNA polymerase II and Spt5 CTD phosphorylation codes. Genes Dev. 28, 1323–1336 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. Pei, Y. & Shuman, S. Interactions between fission yeast mRNA capping enzymes and elongation factor Spt5. J. Biol. Chem. 277, 19639–19648 (2002).

    PubMed  Article  CAS  Google Scholar 

  94. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. Qiu, Y. & Gilmour, D. S. Identification of regions in the Spt5 Subunit of DRB Sensitivity-inducing Factor (DSIF) that are involved in promoter-proximal pausing. J. Biol. Chem. 292, 5555–5570 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. Bernecky, C., Plitzko, J. M. & Cramer, P. Structure of a transcribing RNA polymerase II-DSIF complex reveals a multidentate DNA-RNA clamp. Nat. Struct. Mol. Biol. 24, 809–815 (2017).

    PubMed  Article  CAS  Google Scholar 

  97. Ehara, H. et al. Structure of the complete elongation complex of RNA polymerase II with basal factors. Science 357, 921–924 (2017).

    PubMed  Article  CAS  Google Scholar 

  98. Vos, S. M. et al. Architecture and RNA binding of the human negative elongation factor. eLife 5, e14981 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  99. Jadlowsky, J. K. et al. Negative elongation factor is required for the maintenance of proviral latency but does not induce promoter-proximal pausing of RNA polymerase II on the HIV long terminal repeat. Mol. Cell. Biol. 34, 1911–1928 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  101. Core, L. J. et al. Defining the status of RNA polymerase at promoters. Cell Rep. 2, 1025–1035 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. Yamaguchi, Y., Inukai, N., Narita, T., Wada, T. & Handa, H. Evidence that negative elongation factor represses transcription elongation through binding to a DRB sensitivity-inducing factor/RNA polymerase II complex and RNA. Mol. Cell. Biol. 22, 2918–2927 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. Schaukowitch, K. et al. Enhancer RNA facilitates NELF release from immediate early genes. Mol. Cell 56, 29–42 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. Tan, S., Conaway, R. C. & Conaway, J. W. Dissection of transcription factor TFIIF functional domains required for initiation and elongation. Proc. Natl Acad. Sci. USA 92, 6042–6046 (1995).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. Ishibashi, T. et al. Transcription factors IIS and IIF enhance transcription efficiency by differentially modifying RNA polymerase pausing dynamics. Proc. Natl Acad. Sci. USA 111, 3419–3424 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. Wu, Y. M. et al. Regulation of mammalian transcription by Gdown1 through a novel steric crosstalk revealed by cryo-EM. EMBO J. 31, 3575–3587 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. Mullen Davis, M. A., Guo, J., Price, D. H. & Luse, D. S. Functional interactions of the RNA polymerase II-interacting proteins Gdown1 and TFIIF. J. Biol. Chem. 289, 11143–11152 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  109. DeLaney, E. & Luse, D. S. Gdown1 associates efficiently with RNA Polymerase II after promoter clearance and displaces TFIIF during transcript elongation. PLoS ONE 11, e0163649 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. Kim, J., Guermah, M. & Roeder, R. G. The human PAF1 complex acts in chromatin transcription elongation both independently and cooperatively with SII/TFIIS. Cell 140, 491–503 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  111. Chen, Y. et al. DSIF, the Paf1 complex, and Tat-SF1 have nonredundant, cooperative roles in RNA polymerase II elongation. Genes Dev. 23, 2765–2777 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. Bai, X. et al. TIF1gamma controls erythroid cell fate by regulating transcription elongation. Cell 142, 133–143 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. Chen, F. X. et al. PAF1 regulation of promoter-proximal pause release via enhancer activation. Science 357, 1294–1298 (2017). This study reveals a connection between PAF1 regulating enhancer activation to regulate pause release of nearby genes.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  114. Yu, M. et al. RNA polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA polymerase II. Science 350, 1383–1386 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  115. Jaenicke, L. A. et al. Ubiquitin-dependent turnover of MYC antagonizes MYC/PAF1C complex accumulation to drive transcriptional elongation. Mol. Cell 61, 54–67 (2016).

    PubMed  Article  CAS  Google Scholar 

  116. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. Sehgal, P. B., Darnell, J. E. Jr & Tamm, I. The inhibition by DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) of hnRNA and mRNA production in HeLa cells. Cell 9, 473–480 (1976).

    PubMed  Article  CAS  Google Scholar 

  118. Fujinaga, K. et al. Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element. Mol. Cell. Biol. 24, 787–795 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. Kim, J. B. & Sharp, P. A. Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase. J. Biol. Chem. 276, 12317–12323 (2001).

    PubMed  Article  CAS  Google Scholar 

  120. Marshall, N. F., Peng, J., Xie, Z. & Price, D. H. Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J. Biol. Chem. 271, 27176–27183 (1996).

    PubMed  Article  CAS  Google Scholar 

  121. Sanso, M. et al. P-TEFb regulation of transcription termination factor Xrn2 revealed by a chemical genetic screen for Cdk9 substrates. Genes Dev. 30, 117–131 (2016). This study uses a chemical genetic screen to identify 100 potential substrates of CDK9 that are implicated in various steps of transcription.

  122. Wu, C. H. et al. NELF and DSIF cause promoter proximal pausing on the hsp70 promoter in Drosophila. Genes Dev. 17, 1402–1414 (2003).

    PubMed  Article  CAS  Google Scholar 

  123. Yamada, T. et al. P-TEFb-mediated phosphorylation of hSpt5 C-terminal repeats is critical for processive transcription elongation. Mol. Cell 21, 227–237 (2006).

    PubMed  Article  CAS  Google Scholar 

  124. Smith, E., Lin, C. & Shilatifard, A. The super elongation complex (SEC) and MLL in development and disease. Genes Dev. 25, 661–672 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. Luo, Z., Lin, C. & Shilatifard, A. The super elongation complex (SEC) family in transcriptional control. Nat. Rev. Mol. Cell Biol. 13, 543–547 (2012).

    PubMed  Article  CAS  Google Scholar 

  126. Michels, A. A. et al. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Mol. Cell. Biol. 23, 4859–4869 (2003).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. Zhou, Q., Li, T. & Price, D. H. RNA polymerase II elongation control. Annu. Rev. Biochem. 81, 119–143 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. Lu, H. et al. AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation. Proc. Natl Acad. Sci. USA 111, E15–E24 (2014).

    PubMed  Article  CAS  Google Scholar 

  130. McNamara, R. P. et al. KAP1 recruitment of the 7SK snRNP complex to promoters enables transcription elongation by RNA polymerase II. Mol. Cell 61, 39–53 (2016).

    PubMed  Article  CAS  Google Scholar 

  131. Ji, X. et al. SR proteins collaborate with 7SK and promoter-associated nascent RNA to release paused polymerase. Cell 153, 855–868 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  132. Winter, G. E. et al. BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment. Mol. Cell 67, 5–18.e19 (2017). This study uses acute protein degradation to study the regulation of transcription elongation by BRD4.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  133. Rahman, S. et al. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol. Cell. Biol. 31, 2641–2652 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  134. Devaiah, B. N. et al. BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc. Natl Acad. Sci. USA 109, 6927–6932 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  135. Kanno, T. et al. BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones. Nat. Struct. Mol. Biol. 21, 1047–1057 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. Cho, W. K. et al. Modulation of the Brd4/P-TEFb interaction by the human T-lymphotropic virus type 1 tax protein. J. Virol. 81, 11179–11186 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  138. Garber, M. E. et al. The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein. Genes Dev. 12, 3512–3527 (1998).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. Shilatifard, A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu. Rev. Biochem. 81, 65–95 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  141. Liu, K. et al. The super elongation complex drives neural stem cell fate commitment. Dev. Cell 40, 537–551 e6 (2017). This study shows that SEC can physically interact with and be recruited by the RBPJ (also known as CSL) transcription factor to activate Notch signalling.

    PubMed  Article  CAS  Google Scholar 

  142. Gardini, A. et al. Integrator regulates transcriptional initiation and pause release following activation. Mol. Cell 56, 128–139 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. Wan, L. et al. ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia. Nature 543, 265–269 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. Erb, M. A. et al. Transcription control by the ENL YEATS domain in acute leukaemia. Nature 543, 270–274 (2017). References 143 and 144 reveal that binding of ENL to acetylated histones is required for the recruitment of the SEC and DOT1L to their target genes to promote MLL-rearranged leukaemia.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  145. Zhang, Z. et al. Crosstalk between histone modifications indicates that inhibition of arginine methyltransferase CARM1 activity reverses HIV latency. Nucleic Acids Res. 45, 9348–9360 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  146. Gates, L. A. et al. Acetylation on histone H3 lysine 9 mediates a switch from transcription initiation to elongation. J. Biol. Chem. 292, 14456–14472 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  148. Lens, Z. et al. Solution structure of the N-terminal domain of Mediator subunit MED26 and molecular characterization of its interaction with EAF1 and TAF7. J. Mol. Biol. 429, 3043–3055 (2017).

  149. Hu, D. et al. The little elongation complex functions at initiation and elongation phases of snRNA gene transcription. Mol. Cell 51, 493–505 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  150. Smith, E. R. et al. The little elongation complex regulates small nuclear RNA transcription. Mol. Cell 44, 954–965 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. Takahashi, H. et al. MED26 regulates the transcription of snRNA genes through the recruitment of little elongation complex. Nat. Commun. 6, 5941 (2015).

    PubMed  Article  CAS  Google Scholar 

  152. Talbert, P. B. & Henikoff, S. Histone variants on the move: substrates for chromatin dynamics. Nat. Rev. Mol. Cell Biol. 18, 115–126 (2017).

    PubMed  Article  CAS  Google Scholar 

  153. Lai, W. K. M. & Pugh, B. F. Understanding nucleosome dynamics and their links to gene expression and DNA replication. Nat. Rev. Mol. Cell Biol. 18, 548–562 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  154. Venkatesh, S. & Workman, J. L. Histone exchange, chromatin structure and the regulation of transcription. Nat. Rev. Mol. Cell Biol. 16, 178–189 (2015).

    PubMed  Article  CAS  Google Scholar 

  155. Kornberg, R. D. & Lorch, Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98, 285–294 (1999).

    PubMed  Article  CAS  Google Scholar 

  156. Kireeva, M. L. et al. Nucleosome remodeling induced by RNA polymerase II: loss of the H2A/H2B dimer during transcription. Mol. Cell 9, 541–552 (2002).

    PubMed  Article  CAS  Google Scholar 

  157. Orphanides, G., LeRoy, G., Chang, C. H., Luse, D. S. & Reinberg, D. FACT, a factor that facilitates transcript elongation through nucleosomes. Cell 92, 105–116 (1998).

    PubMed  Article  CAS  Google Scholar 

  158. Bondarenko, V. A. et al. Nucleosomes can form a polar barrier to transcript elongation by RNA polymerase II. Mol. Cell 24, 469–479 (2006).

    PubMed  Article  CAS  Google Scholar 

  159. Saunders, A. et al. Tracking FACT and the RNA polymerase II elongation complex through chromatin in vivo. Science 301, 1094–1096 (2003).

    PubMed  Article  CAS  Google Scholar 

  160. Hondele, M. et al. Structural basis of histone H2A-H2B recognition by the essential chaperone FACT. Nature 499, 111–114 (2013).

    PubMed  Article  CAS  Google Scholar 

  161. Kemble, D. J., McCullough, L. L., Whitby, F. G., Formosa, T. & Hill, C. P. FACT disrupts nucleosome structure by binding H2A-H2B with conserved peptide motifs. Mol. Cell 60, 294–306 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  162. Petesch, S. J. & Lis, J. T. Overcoming the nucleosome barrier during transcript elongation. Trends Genet. 28, 285–294 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  163. Teves, S. S., Weber, C. M. & Henikoff, S. Transcribing through the nucleosome. Trends Biochem. Sci. 39, 577–586 (2014).

    PubMed  Article  CAS  Google Scholar 

  164. Simic, R. et al. Chromatin remodeling protein Chd1 interacts with transcription elongation factors and localizes to transcribed genes. EMBO J. 22, 1846–1856 (2003).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  165. Kaplan, C. D., Holland, M. J. & Winston, F. Interaction between transcription elongation factors and mRNA 3′-end formation at the Saccharomyces cerevisiae GAL10-GAL7 locus. J. Biol. Chem. 280, 913–922 (2005).

    PubMed  Article  CAS  Google Scholar 

  166. Pruneski, J. A., Hainer, S. J., Petrov, K. O. & Martens, J. A. The Paf1 complex represses SER3 transcription in Saccharomyces cerevisiae by facilitating intergenic transcription-dependent nucleosome occupancy of the SER3 promoter. Eukaryot. Cell 10, 1283–1294 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  167. Pavri, R. et al. Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II. Cell 125, 703–717 (2006).

    PubMed  Article  CAS  Google Scholar 

  168. Krogan, N. J. et al. The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation. Mol. Cell 11, 721–729 (2003).

    PubMed  Article  CAS  Google Scholar 

  169. Wood, A., Schneider, J., Dover, J., Johnston, M. & Shilatifard, A. The Paf1 complex is essential for histone monoubiquitination by the Rad6-Bre1 complex, which signals for histone methylation by COMPASS and Dot1p. J. Biol. Chem. 278, 34739–34742 (2003).

    PubMed  Article  CAS  Google Scholar 

  170. Ng, H. H., Dole, S. & Struhl, K. The Rtf1 component of the Paf1 transcriptional elongation complex is required for ubiquitination of histone H2B. J. Biol. Chem. 278, 33625–33628 (2003).

    PubMed  Article  CAS  Google Scholar 

  171. Grohmann, D. et al. The initiation factor TFE and the elongation factor Spt4/5 compete for the RNAP clamp during transcription initiation and elongation. Mol. Cell 43, 263–274 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  172. Klein, B. J. et al. RNA polymerase and transcription elongation factor Spt4/5 complex structure. Proc. Natl Acad. Sci. USA 108, 546–550 (2011).

    PubMed  Article  Google Scholar 

  173. Shetty, A. et al. Spt5 plays vital roles in the control of sense and antisense transcription elongation. Mol. Cell 66, 77–88.e5 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  174. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  175. Fuchs, G., Hollander, D., Voichek, Y., Ast, G. & Oren, M. Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate. Genome Res. 24, 1572–1583 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  176. Vakoc, C. R., Sachdeva, M. M., Wang, H. & Blobel, G. A. Profile of histone lysine methylation across transcribed mammalian chromatin. Mol. Cell. Biol. 26, 9185–9195 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  177. Lee, J. S., Smith, E. & Shilatifard, A. The language of histone crosstalk. Cell 142, 682–685 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  178. Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    PubMed  Article  CAS  Google Scholar 

  179. Batta, K., Zhang, Z., Yen, K., Goffman, D. B. & Pugh, B. F. Genome-wide function of H2B ubiquitylation in promoter and genic regions. Genes Dev. 25, 2254–2265 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  180. Lee, J. S. et al. Codependency of H2B monoubiquitination and nucleosome reassembly on Chd1. Genes Dev. 26, 914–919 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  181. Tanny, J. C., Erdjument-Bromage, H., Tempst, P. & Allis, C. D. Ubiquitylation of histone H2B controls RNA polymerase II transcription elongation independently of histone H3 methylation. Genes Dev. 21, 835–847 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  182. Segala, G., Bennesch, M. A., Pandey, D. P., Hulo, N. & Picard, D. Monoubiquitination of histone H2B blocks eviction of histone variant H2A.Z. from inducible enhancers. Mol. Cell 64, 334–346 (2016).

    PubMed  Article  CAS  Google Scholar 

  183. Xie, W. et al. RNF40 regulates gene expression in an epigenetic context-dependent manner. Genome Biol. 18, 32 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  184. McDaniel, S. L. & Strahl, B. D. Shaping the cellular landscape with Set2/SETD2 methylation. Cell. Mol. Life Sci. 74, 3317–3334 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  185. Carrozza, M. J. et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123, 581–592 (2005).

    PubMed  Article  CAS  Google Scholar 

  186. Smolle, M. et al. Chromatin remodelers Isw1 and Chd1 maintain chromatin structure during transcription by preventing histone exchange. Nat. Struct. Mol. Biol. 19, 884–892 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  187. Baubec, T. et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520, 243–247 (2015).

    PubMed  Article  CAS  Google Scholar 

  188. Neri, F. et al. Intragenic DNA methylation prevents spurious transcription initiation. Nature 543, 72–77 (2017). References 187 and 188 demonstrate that DNMT3B recognizes SETD2-mediated H3K36me3 and catalyses intragenic DNA methylation to ensure the fidelity of gene transcription.

    PubMed  Article  CAS  Google Scholar 

  189. Zhu, B. et al. The human PAF complex coordinates transcription with events downstream of RNA synthesis. Genes Dev. 19, 1668–1673 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  190. Wang, E. et al. Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia. Proc. Natl Acad. Sci. USA 110, 3901–3906 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  191. Nakanishi, S. et al. Histone H2BK123 monoubiquitination is the critical determinant for H3K4 and H3K79 trimethylation by COMPASS and Dot1. J. Cell Biol. 186, 371–377 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  192. Lee, J. S. et al. Histone crosstalk between H2B monoubiquitination and H3 methylation mediated by COMPASS. Cell 131, 1084–1096 (2007).

    PubMed  Article  CAS  Google Scholar 

  193. Mohan, M. et al. Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev. 24, 574–589 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  194. Dillon, S. C., Zhang, X., Trievel, R. C. & Cheng, X. The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 6, 227 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  195. Yankulov, K., Blau, J., Purton, T., Roberts, S. & Bentley, D. L. Transcriptional elongation by RNA polymerase II is stimulated by transactivators. Cell 77, 749–759 (1994).

    PubMed  Article  CAS  Google Scholar 

  196. Smith, E. & Shilatifard, A. Enhancer biology and enhanceropathies. Nat. Struct. Mol. Biol. 21, 210–219 (2014).

    PubMed  Article  CAS  Google Scholar 

  197. Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol. 16, 144–154 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  198. Rollins, R. A., 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, 3100–3111 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  199. Phillips-Cremins, J. E. et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153, 1281–1295 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  200. Kagey, M. H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  201. Schaaf, C. A. et al. Genome-wide control of RNA polymerase II activity by cohesin. PLoS Genet. 9, e1003382 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  202. Fay, A. et al. Cohesin selectively binds and regulates genes with paused RNA polymerase. Curr. Biol. 21, 1624–1634 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  203. Wu, Y. et al. Drosophila Nipped-B mutants model cornelia de lange syndrome in growth and behavior. PLoS Genet. 11, e1005655 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  204. Izumi, K. et al. Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat. Genet. 47, 338–344 (2015). This study identifies mutations of AFF4 that stabilize the protein as the cause of CHOPS syndrome.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  205. Jishage, M. et al. Transcriptional regulation by Pol II(G) involving mediator and competitive interactions of Gdown1 and TFIIF with Pol II. Mol. Cell 45, 51–63 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  206. Galbraith, M. D. et al. HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia. Cell 153, 1327–1339 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  207. Donner, A. J., Ebmeier, C. C., Taatjes, D. J. & Espinosa, J. M. CDK8 is a positive regulator of transcriptional elongation within the serum response network. Nat. Struct. Mol. Biol. 17, 194–201 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  208. Herz, H. M. et al. Enhancer-associated H3K4 monomethylation by trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev. 26, 2604–2620 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  209. Hu, D. et al. The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol. Cell. Biol. 33, 4745–4754 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  210. Tie, F. et al. CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing. Development 136, 3131–3141 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  211. Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 107, 21931–21936 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  212. Shen, Y. et al. A map of the cis-regulatory sequences in the mouse genome. Nature 488, 116–120 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  213. Flynn, R. A. et al. 7SK-BAF axis controls pervasive transcription at enhancers. Nat. Struct. Mol. Biol. 23, 231–238 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  214. Hertweck, A. et al. T-Bet activates Th1 genes through mediator and the super elongation complex. Cell Rep. 15, 2756–2770 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  215. Loven, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  216. Lin, C., Garruss, A. S., Luo, Z., Guo, F. & Shilatifard, A. The RNA Pol II elongation factor Ell3 marks enhancers in ES cells and primes future gene activation. Cell 152, 144–156 (2013).

    PubMed  Article  CAS  Google Scholar 

  217. Pommier, Y., Sun, Y., Huang, S. N. & Nitiss, J. L. Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. Nat. Rev. Mol. Cell Biol. 17, 703–721 (2016).

    PubMed  Article  CAS  Google Scholar 

  218. Corless, S. & Gilbert, N. Effects of DNA supercoiling on chromatin architecture. Biophys. Rev. 8, 51–64 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  219. Bunch, H. et al. Transcriptional elongation requires DNA break-induced signalling. Nat. Commun. 6, 10191 (2015).

    PubMed  Article  CAS  Google Scholar 

  220. Ju, B. G. et al. A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science 312, 1798–1802 (2006).

    PubMed  Article  CAS  Google Scholar 

  221. Madabhushi, R. et al. Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161, 1592–1605 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  222. Gomez-Herreros, F. et al. TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nat. Genet. 46, 516–521 (2014).

    PubMed  Article  CAS  Google Scholar 

  223. Zeng, Z., Cortes-Ledesma, F., El Khamisy, S. F. & Caldecott, K. W. TDP2/TTRAP is the major 5′-tyrosyl DNA phosphodiesterase activity in vertebrate cells and is critical for cellular resistance to topoisomerase II-induced DNA damage. J. Biol. Chem. 286, 403–409 (2011).

    PubMed  Article  CAS  Google Scholar 

  224. Baranello, L. et al. RNA polymerase II regulates topoisomerase 1 activity to favor efficient transcription. Cell 165, 357–371 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  225. Li, M., Pokharel, S., Wang, J. T., Xu, X. & Liu, Y. RECQ5-dependent SUMOylation of DNA topoisomerase I prevents transcription-associated genome instability. Nat. Commun. 6, 6720 (2015).

    PubMed  Article  CAS  Google Scholar 

  226. Solier, S. et al. Transcription poisoning by topoisomerase I is controlled by gene length, splice sites, and miR-142-3p. Cancer Res. 73, 4830–4839 (2013).

    PubMed  Article  CAS  Google Scholar 

  227. King, I. F. et al. Topoisomerases facilitate transcription of long genes linked to autism. Nature 501, 58–62 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  228. Zhang, X. et al. Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis. Nat. Commun. 8, 15908 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  229. Skourti-Stathaki, K. & Proudfoot, N. J. A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression. Genes Dev. 28, 1384–1396 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  230. Tuduri, S. et al. Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription. Nat. Cell Biol. 11, 1315–1324 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  231. Groh, M., Lufino, M. M., Wade-Martins, R. & Gromak, N. R-Loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome. PLoS Genet. 10, e1004318 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  232. Saponaro, M. et al. RECQL5 controls transcript elongation and suppresses genome instability associated with transcription stress. Cell 157, 1037–1049 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  233. Wilson-Sali, T. & Hsieh, T. S. Preferential cleavage of plasmid-based R-loops and D-loops by Drosophila topoisomerase IIIbeta. Proc. Natl Acad. Sci. USA 99, 7974–7979 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  234. Ahmad, M. et al. Topoisomerase 3beta is the major topoisomerase for mRNAs and linked to neurodevelopment and mental dysfunction. Nucleic Acids Res. 45, 2704–2713 (2017).

    PubMed  CAS  Google Scholar 

  235. Yang, Y. et al. Arginine methylation facilitates the recruitment of TOP3B to chromatin to prevent R loop accumulation. Mol. Cell 53, 484–497 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  236. Siaw, G. E., Liu, I. F., Lin, P. Y., Been, M. D. & Hsieh, T. S. DNA and RNA topoisomerase activities of Top3beta are promoted by mediator protein tudor domain-containing protein 3. Proc. Natl Acad. Sci. USA 113, E5544–E5551 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  237. Goto-Ito, S., Yamagata, A., Takahashi, T. S., Sato, Y. & Fukai, S. Structural basis of the interaction between topoisomerase IIIbeta and the TDRD3 auxiliary factor. Sci. Rep. 7, 42123 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  238. Ray Chaudhuri, A. & Nussenzweig, A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol. 18, 610–621 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  239. Hottiger, M. O. Nuclear ADP-ribosylation and its role in chromatin plasticity, cell differentiation, and epigenetics. Annu. Rev. Biochem. 84, 227–263 (2015).

    PubMed  Article  CAS  Google Scholar 

  240. Gupte, R., Liu, Z. & Kraus, W. L. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes. Genes Dev. 31, 101–126 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  241. Wright, R. H. et al. ADP-ribose-derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling. Science 352, 1221–1225 (2016).

    PubMed  Article  CAS  Google Scholar 

  242. Gibson, B. A. et al. Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation. Science 353, 45–50 (2016). This study utilizes a chemical genetic strategy and identifies hundreds of substrates of PARPs, many of which are involved in transcription elongation, including the NELF complex.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  243. Leutert, M., Pedrioli, D. M. & Hottiger, M. O. Identification of PARP-specific ADP-ribosylation targets reveals a regulatory function for ADP-ribosylation in transcription elongation. Mol. Cell 63, 181–183 (2016).

    PubMed  Article  CAS  Google Scholar 

  244. Calderwood, S. K. A critical role for topoisomerase IIb and DNA double strand breaks in transcription. Transcription 7, 75–83 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  245. Huang, J. Y. et al. Modulation of nucleosome-binding activity of FACT by poly(ADP-ribosyl)ation. Nucleic Acids Res. 34, 2398–2407 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  246. Heo, K. et al. FACT-mediated exchange of histone variant H2AX regulated by phosphorylation of H2AX and ADP-ribosylation of Spt16. Mol. Cell 30, 86–97 (2008).

    PubMed  Article  CAS  Google Scholar 

  247. Gao, F., Kwon, S. W., Zhao, Y. & Jin, Y. PARP1 poly(ADP-ribosyl)ates Sox2 to control Sox2 protein levels and FGF4 expression during embryonic stem cell differentiation. J. Biol. Chem. 284, 22263–22273 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  248. Krishnakumar, R. & Kraus, W. L. PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway. Mol. Cell 39, 736–749 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  249. Kidder, B. L., Hu, G. & Zhao, K. KDM5B focuses H3K4 methylation near promoters and enhancers during embryonic stem cell self-renewal and differentiation. Genome Biol. 15, R32 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  250. Liu, Z. & Kraus, W. L. Catalytic-independent functions of PARP-1 determine Sox2 pioneer activity at intractable genomic loci. Mol. Cell 65, 589–603.9 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  251. Chou, D. M. et al. A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. Proc. Natl Acad. Sci. USA 107, 18475–18480 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  252. Spruijt, C. G. et al. ZMYND8 co-localizes with NuRD on target genes and regulates poly(ADP-Ribose)-dependent recruitment of GATAD2A/NuRD to sites of DNA damage. Cell Rep. 17, 783–798 (2016).

    PubMed  Article  CAS  Google Scholar 

  253. Kwiatkowski, N. et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511, 616–620 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  254. Pelish, H. E. et al. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 526, 273–276 (2015). This study shows that inhibition of the Mediator-associated kinases CDK8 and CDK19 with cortistatin A leads to activation of super-enhancers and upregulation of super-enhancer-associated genes.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  255. Cee, V. J., Chen, D. Y., Lee, M. R. & Nicolaou, K. C. Cortistatin A is a high-affinity ligand of protein kinases ROCK, CDK8, and CDK11. Angew. Chem. Int. Ed Engl. 48, 8952–8957 (2009).

    PubMed  Article  CAS  Google Scholar 

  256. Chao, S. H. et al. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J. Biol. Chem. 275, 28345–28348 (2000).

    PubMed  Article  CAS  Google Scholar 

  257. Miller, T. E. et al. Transcription elongation factors represent in vivo cancer dependencies in glioblastoma. Nature 547, 355–359 (2017). This study uses an in vivo functional screening strategy and demonstrates the requirement of many pausing and elongation factors for glioblastoma cell survival.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  258. Liang, K. et al. Therapeutic targeting of MLL degradation pathways in MLL-rearranged leukemia. Cell 168, 59–72.e13 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  259. Kuehner, J. N., Pearson, E. L. & Moore, C. Unravelling the means to an end: RNA polymerase II transcription termination. Nat. Rev. Mol. Cell Biol. 12, 283–294 (2011).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  260. Porrua, O. & Libri, D. Transcription termination and the control of the transcriptome: why, where and how to stop. Nat. Rev. Mol. Cell Biol. 16, 190–202 (2015).

    PubMed  Article  CAS  Google Scholar 

  261. Fong, N. et al. Effects of transcription elongation rate and Xrn2 exonuclease activity on RNA polymerase II termination suggest widespread kinetic competition. Mol. Cell 60, 256–267 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  262. Zhang, H., Rigo, F. & Martinson, H. G. Poly(A) signal-dependent transcription termination occurs through a conformational change mechanism that does not require cleavage at the poly(A) site. Mol. Cell 59, 437–448 (2015).

    PubMed  Article  CAS  Google Scholar 

  263. Libri, D. Endless quarrels at the end of genes. Mol. Cell 60, 192–194 (2015).

    PubMed  Article  CAS  Google Scholar 

  264. Ni, Z., Schwartz, B. E., Werner, J., Suarez, J. R. & Lis, J. T. Coordination of transcription, RNA processing, and surveillance by P-TEFb kinase on heat shock genes. Mol. Cell 13, 55–65 (2004).

    PubMed  Article  CAS  Google Scholar 

  265. Laitem, C. et al. CDK9 inhibitors define elongation checkpoints at both ends of RNA polymerase II-transcribed genes. Nat. Struct. Mol. Biol. 22, 396–403 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  266. Skourti-Stathaki, K., Kamieniarz-Gdula, K. & Proudfoot, N. J. R-Loops induce repressive chromatin marks over mammalian gene terminators. Nature 516, 436–439 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  267. Skourti-Stathaki, K., Proudfoot, N. J. & Gromak, N. Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol. Cell 42, 794–805 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  268. Zhao, D. Y. et al. SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination. Nature 529, 48–53 (2016).

    PubMed  Article  CAS  Google Scholar 

  269. Xu, Y. et al. Architecture of the RNA polymerase II-Paf1C-TFIIS transcription elongation complex. Nat. Commun. 8, 15741 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

F.X.C., E.R.S. and A.S. researched data for the article, made substantial contributions to the discussion of content, wrote the article and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Ali Shilatifard.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Super elongation complex

(SEC). A complex containing the most active form of positive transcription elongation factor-b; required for almost all rapid inductions of transcription and for release of paused RNA polymerase II.

Pausing index

An estimate of RNA polymerase II (Pol II) promoter-proximal pausing; the ratio of Pol II occupancy at the promoter-proximal region compared with the gene body.

Travelling ratio

The ratio of gene-body RNA polymerase II (Pol II) to promoter-proximal Pol II.

Initiating Pol II

RNA polymerase II that is recruited by the general transcription factors and is involved in promoter melting before being released for transcription.

Paused Pol II

RNA polymerase II that has initiated non-productive transcription and is transiently pausing at the promoter-proximal region.

Bisulfite sequencing

Bisulfite deaminates unmethylated DNA cytosine into uracil, which can be used to infer the position of methylated cytosine through sequencing.

TATA box

A short AT-rich motif found in many RNA polymerase II promoters; bound by the general transcription factor TATA-binding protein.

G-quadruplex

(G4). A highly stable nucleic acid structure comprising two or more stacked guanine tetrads. Intramolecular G-quadruplexes formed in nascent RNA can contribute to RNA polymerase II pausing.

Mediator complex

A large multiprotein complex that interacts with transcription factors and RNA polymerase II. Mediator can promote enhancer–promoter looping to activate transcription and can also recruit transcription elongation factors.

Auxin-inducible degradation

In cells expressing a plant auxin-inducible E3 ubiquitin ligase, any protein of interest can be tagged for rapid degraded upon addition of auxin to the medium.

Acute protein degradation

Experimentally induced degradation of proteins by targeting them for proteasomal degradation.

Integrator complex

A large multiprotein complex found only in metazoans that can directly interact with RNA polymerase II; facilitates transcription and 3′-end processing of enhancer RNAs and small nuclear RNAs and recruitment of the super elongation complex to immediate early-response genes.

Nucleosome breathing

A property of nucleosomes whereby DNA at the edges of the histone core transiently unwrap and rewrap.

Pol II clamp

Part of the RNA polymerase II (Pol II) complex comprising the amino-terminal regions of RNA Pol II subunit 1 (Rpb1) and Rpb2, and the carboxy-terminal region of Rpb6, which swings over the Pol II active-site cleft to encase the DNA template and nascent RNA.

Cornelia de Lange syndrome

A developmental syndrome caused by heterozygous germline loss-of-function mutations in the cohesin loading protein nipped-B-like protein or in structural components of the cohesin ring.

CHOPS syndrome

A developmental syndrome with a similar phenotype to Cornelia de Lange syndrome that is caused by germline gain-of-function mutations in the super elongation complex scaffolding protein AF4/FMR2 family member 4.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, F.X., Smith, E.R. & Shilatifard, A. Born to run: control of transcription elongation by RNA polymerase II. Nat Rev Mol Cell Biol 19, 464–478 (2018). https://doi.org/10.1038/s41580-018-0010-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-018-0010-5

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing