Getting up to speed with transcription elongation by RNA polymerase II (original) (raw)

• Kwak, H. & Lis, J. T. Control of transcriptional elongation. Annu. Rev. Genet. 47, 483–508 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Adelman, K. & Lis, J. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nature Rev. Genet. 13, 720–731 (2012).
  CAS PubMed Google Scholar
• 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). In this study, pausing was mapped at the genome-wide level with base-pair resolution, showing the dependency of strong promoter-proximal pausing on core promoter elements.
  CAS PubMed PubMed Central Google Scholar
• Li, J. & Gilmour, D. Distinct mechanisms of transcriptional pausing orchestrated by GAGA factor and M1BP, a novel transcription factor. EMBO J. 32, 1829–1841 (2013).
  CAS PubMed PubMed Central Google Scholar
• Weber, C. M., Ramachandran, S. & Henikoff, S. Nucleosomes are context-specific, H2A.Z-modulated barriers to RNA polymerase. Mol. Cell 53, 819–830 (2014).
  CAS PubMed Google Scholar
• Peterlin, B. & Price, D. Controlling the elongation phase of transcription with P-TEFb. Mol. Cell 23, 297–305 (2006).
  CAS PubMed Google Scholar
• Zhou, Q., Li, T. & Price, D. H. RNA polymerase II elongation control. Annu. Rev. Biochem. 81, 119–143 (2012).
  CAS PubMed PubMed Central Google Scholar
• Lis, J., Mason, P., Peng, J., Price, D. & Werner, J. P-TEFb kinase recruitment and function at heat shock loci. Genes Dev. 14, 792–803 (2000).
  CAS PubMed PubMed Central Google Scholar
• 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). This study measures elongation rates genome-wide and shows that the half-lives of paused Pol II complexes on 3,181 genes are uniformly long with an average of 7 minutes.
  PubMed PubMed Central Google Scholar
• Danko, C. et al. Signaling pathways differentially affect RNA polymerase II initiation, pausing, and elongation rate in cells. Mol. Cell 50, 212–222 (2013).
  CAS PubMed PubMed Central Google Scholar
• Alexander, R., Innocente, S., Barrass, J. & Beggs, J. Splicing-dependent RNA polymerase pausing in yeast. Mol. Cell 40, 582–593 (2010).
  CAS PubMed PubMed Central Google Scholar
• Veloso, A. et al. Rate of elongation by RNA polymerase II is associated with specific gene features and epigenetic modifications. Genome Res. 24, 896–905 (2014).
  CAS PubMed PubMed Central Google Scholar
• Fuchs, G. et al. 4sUDRB-seq: measuring genomewide transcriptional elongation rates and initiation frequencies within cells. Genome Biol. 15, R69 (2014).
  PubMed PubMed Central Google Scholar
• Saponaro, M. et al. RECQL5 controls transcript elongation and suppresses genome instability associated with transcription stress. Cell 157, 1037–1049 (2014). This manuscript documents that RECQL5 slows down transcript elongation and suppresses genome rearrangements at common fragile sites.
  CAS PubMed PubMed Central Google Scholar
• Dujardin, G. et al. How slow RNA polymerase II elongation favors alternative exon skipping. Mol. Cell 54, 683–690 (2014).
  CAS PubMed Google Scholar
• Schor, I., Fiszbein, A., Petrillo, E. & Kornblihtt, A. Intragenic epigenetic changes modulate NCAM alternative splicing in neuronal differentiation. EMBO J. 32, 2264–2274 (2013).
  CAS PubMed PubMed Central Google Scholar
• Mata, M. de la et al. A slow RNA polymerase II affects alternative splicing in vivo. Mol. Cell 12, 525–532 (2003).
  PubMed Google Scholar
• Moehle, E. A., Braberg, H., Krogan, N. J. & Guthrie, C. Adventures in time and space: splicing efficiency and RNA polymerase II elongation rate. RNA Biol. 11, 313–319 (2014).
  CAS PubMed PubMed Central Google Scholar
• Plant, K., Dye, M., Lafaille, C. & Proudfoot, N. Strong polyadenylation and weak pausing combine to cause efficient termination of transcription in the human gamma-globin gene. Mol. Cell. Biol. 25, 3276–3285 (2005).
  CAS PubMed PubMed Central Google Scholar
• Gromak, N., West, S. & Proudfoot, N. Pause sites promote transcriptional termination of mammalian, RNA polymerase II. Mol. Cell. Biol. 26, 3986–3996 (2006).
  CAS PubMed PubMed Central Google Scholar
• Skourti-Stathaki, K., Kamieniarz-Gdula, K. & Proudfoot, N. J. R-loops induce repressive chromatin marks over mammalian gene terminators. Nature 516, 436–439 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Hazelbaker, D., Marquardt, S., Wlotzka, W. & Buratowski, S. Kinetic competition between RNA Polymerase II and Sen1-dependent transcription termination. Mol. Cell 49, 55–66 (2013).
  CAS PubMed Google Scholar
• Sainsbury, S., Bernecky, S. & Cramer, P. Structural basis of transcription initiation by RNA polymerase II. Nature Rev. Mol. Cell. Biol. 16, 129–143 (2015).
  CAS Google Scholar
• Porrua, O. & Libri, D. Transcription termination and the control of the transcriptome: why, where and how to stop. Nature Rev. Mol. Cell. Biol. 16, 190–202 (2015).
  CAS Google Scholar
• Venkatesh, S. S. & Workman, J. L. Histone exchange, chromatin structure and the regulation of transcription. Nature Rev. Mol. Cell. Biol. 16, 178–189 (2015).
  CAS Google Scholar
• Ehrensberger, A. H., Kelly, G. P. & Svejstrup, J. Q. Mechanistic interpretation of promoter-proximal peaks and RNAPII density maps. Cell 154, 713–715 (2013).
  CAS PubMed Google Scholar
• Venters, B. & Pugh, B. Genomic organization of human transcription initiation complexes. Nature 502, 53–58 (2013).
  CAS PubMed PubMed Central Google Scholar
• Core, L. J. et al. Defining the status of RNA polymerase at promoters. Cell Rep. 2, 1025–1035 (2012).
  CAS PubMed PubMed Central Google Scholar
• Rahl, P. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010).
  CAS PubMed PubMed Central Google Scholar
• 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). This study reports that promoter-paused elongation complexes are highly stable, with half-lives of minutes in D. melanogaster.
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Min, I. M. et al. Regulating RNA polymerase pausing and transcription elongation in embryonic stem cells. Genes Dev. 25, 742–754 (2011).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Gilchrist, D. et al. Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation. Cell 143, 540–551 (2010).
  CAS PubMed PubMed Central Google Scholar
• Lee, H., Kraus, K., Wolfner, M. & Lis, J. DNA sequence requirements for generating paused polymerase at the start of hsp70. Genes Dev. 6, 284–295 (1992).
  CAS PubMed Google Scholar
• Shopland, L., Hirayoshi, K., Fernandes, M. & Lis, J. 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).
  CAS PubMed Google Scholar
• Kouzine, F. et al. Global regulation of promoter melting in naive lymphocytes. Cell 153, 988–999 (2013). This genome-wide analysis of resting lymphocytes identifies promoter melting as a third major rate-limiting step in transcription (following PIC formation and pause release).
  CAS PubMed PubMed Central Google Scholar
• Soutoglou, E. & Talianidis, I. Coordination of PIC assembly and chromatin remodeling during differentiation-induced gene activation. Science 295, 1901–1904 (2002).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Wagschal, A. et al. Microprocessor, Setx, Xrn2, and Rrp6 co-operate to induce premature termination of transcription by RNAPII. Cell 150, 1147–1157 (2012).
  CAS PubMed PubMed Central Google Scholar
• Cheng, B. et al. Functional association of Gdown1 with RNA polymerase II poised on human genes. Mol. Cell 45, 38–50 (2012).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Davis, M., Guo, J., Price, D. & Luse, D. Functional interactions of the RNA polymerase II-interacting proteins Gdown1 and TFIIF. J. Biol. Chem. 289, 11143–11152 (2014).
  Google Scholar
• 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 Google Scholar
• Buckley, M. S., Kwak, H., Zipfel, W. R. & Lis, J. T. Kinetics of promoter Pol II on Hsp70 reveal stable pausing and key insights into its regulation. Genes Dev. 28, 14–19 (2014).
  CAS PubMed PubMed Central Google Scholar
• Saunders, A., Core, L., Sutcliffe, C., Lis, J. & Ashe, H. Extensive polymerase pausing during Drosophila axis patterning enables high-level and pliable transcription. Genes Dev. 27, 1146–1158 (2013).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Guenther, M., Levine, S., Boyer, L., Jaenisch, R. & Young, R. A. Chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).
  CAS PubMed PubMed Central Google Scholar
• Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nature Genet. 39, 1512–1516 (2007).
  CAS PubMed Google Scholar
• Lagha, M. et al. Paused pol II coordinates tissue morphogenesis in the Drosophila embryo. Cell 153, 976–987 (2013).
  CAS PubMed PubMed Central Google Scholar
• Kapanidis, A. N. et al. Initial transcription by RNA polymerase proceeds through a DNA-scrunching mechanism. Science 314, 1144–1147 (2006).
  PubMed PubMed Central Google Scholar
• Pal, M., Ponticelli, A. & Luse, D. The role of the transcription bubble & TFIIB in promoter clearance by RNA polymerase II. Mol. Cell 19, 101–110 (2005).
  CAS PubMed Google Scholar
• Strobel, E. & Roberts, J. Regulation of promoter-proximal transcription elongation: enhanced DNA scrunching drives λQ antiterminator-dependent escape from a σ70-dependent pause. Nucleic Acids Res. 42, 5097–5108 (2014).
  CAS PubMed PubMed Central Google Scholar
• Hendrix, D. A., Hong, J.-W. 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).
  CAS PubMed PubMed Central Google Scholar
• Core, L. et al. Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nature Genet. 46, 1311–1320 (2014).
  CAS PubMed Google Scholar
• Li, J. et al. Kinetic competition between elongation rate and binding of NELF controls promoter-proximal pausing. Mol. Cell 50, 711–722 (2013).
  CAS PubMed PubMed Central Google Scholar
• Hargreaves, D., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145 (2009).
  CAS PubMed PubMed Central Google Scholar
• Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. The selection and function of cell type-specific enhancers. Nature Rev. Mol. Cell. Biol. 16, 144–154 (2015).
  CAS Google Scholar
• Allen, B. L. & Taatjes, D. J. The Mediator complex: a central integrator of transcription. Nature Rev. Mol. Cell. Biol. 16, 155–166 (2015).
  CAS Google Scholar
• Takahashi, H. et al. Human mediator subunit MED26 functions as a docking site for transcription elongation factors. Cell 146, 92–104 (2011).
  CAS PubMed PubMed Central Google Scholar
• Ghavi-Helm, Y. et al. Enhancer loops appear stable during development and are associated with paused polymerase. Nature 512, 96–100 (2014).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Farkas, G., Leibovitch, B. & Elgin, S. Chromatin organization and transcriptional control of gene expression in Drosophila. Gene 253, 117–136 (2000).
  CAS PubMed Google Scholar
• Chopra, V. S. et al. Transcriptional activation by GAGA factor is through its direct interaction with dmTAF3. Dev. Biol. 317, 660–670 (2008).
  CAS PubMed Google Scholar
• Blau, J. et al. Three functional classes of transcriptional activation domain. Mol. Cell. Biol. 16, 2044–2055 (1996).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Bunch, H. et al. TRIM28 regulates RNA polymerase II promoter-proximal pausing and pause release. Nature Struct. Mol. Biol. 21, 876–883 (2014).
  CAS Google Scholar
• Jiang, L. et al. Polo-like kinase 1 inhibits the activity of positive transcription elongation factor of RNA Pol II b (P-TEFb). PloS ONE 8, e72289 (2013).
  CAS PubMed PubMed Central Google Scholar
• Smith, E., Lin, C. & Shilatifard, A. The super elongation complex (SEC) and MLL in development and disease. Genes Dev. 25, 661–672 (2011).
  CAS PubMed PubMed Central Google Scholar
• Itzen, F., Greifenberg, A., Bosken, C. & Geyer, M. Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation. Nucleic Acids Res. 42, 7577–7590 (2014).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Zou, Z. et al. Brd4 maintains constitutively active NF-κB in cancer cells by binding to acetylated RelA. Oncogene 33, 2395–2404 (2014).
  CAS PubMed Google Scholar
• Huang, B., Yang, X.-D. D., Zhou, M.-M. M., Ozato, K. & Chen, L.-F. F. Brd4 coactivates transcriptional activation of NF-κB via specific binding to acetylated RelA. Mol. Cell. Biol. 29, 1375–1387 (2009).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Lin, C. et al. Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC). Genes Dev. 25, 1486–1498 (2011).
  CAS PubMed PubMed Central Google Scholar
• Smith, E. et al. The little elongation complex regulates small nuclear RNA transcription. Mol. Cell 44, 954–965 (2011).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Luo, Z., Lin, C. & Shilatifard, A. The super elongation complex (SEC) family in transcriptional control. Nature Rev. Mol. Cell. Biol. 13, 543–547 (2012).
  CAS Google Scholar
• Gardini, A. et al. Integrator regulates transcriptional initiation and pause release following activation. Mol. Cell 56, 128–139 (2014).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Wier, A., Mayekar, M., Héroux, A., Arndt, K. & VanDemark, A. Structural basis for Spt5-mediated recruitment of the Paf1 complex to chromatin. Proc. Natl Acad. Sci. USA 110, 17290–17295 (2013).
  CAS PubMed PubMed Central Google Scholar
• He, N. et al. Human Polymerase-Associated Factor complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatin. Proc. Natl Acad. Sci. USA 108, E636–645 (2011).
  CAS PubMed PubMed Central Google Scholar
• Flajollet, S. et al. The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors. PloS ONE 8, e64880 (2013).
  CAS PubMed PubMed Central Google Scholar
• Diamant, G. & Dikstein, R. Transcriptional control by NF-κB: elongation in focus. Biochim. Biophys. Acta 1829, 937–945 (2013).
  CAS PubMed Google Scholar
• Nowak, D. et al. RelA Ser276 phosphorylation is required for activation of a subset of NF-κB-dependent genes by recruiting cyclin-dependent kinase 9/cyclin T1 complexes. Mol. Cell. Biol. 28, 3623–3638 (2008).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Mertz, J. et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci. USA 108, 16669–16674 (2011).
  CAS PubMed PubMed Central Google Scholar
• Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013). This study shows that exceptionally high levels of the co-activators Mediator and BRD4 are associated with super-enhancers that drive the expression of key oncogenes.
  PubMed PubMed Central Google Scholar
• Delmore, J. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).
  CAS PubMed PubMed Central Google Scholar
• Oeckinghaus, A., Hayden, M. & Ghosh, S. Crosstalk in NF-κB signaling pathways. Nature Immunol. 12, 695–708 (2011).
  CAS Google Scholar
• Fang, L. et al. ATM regulates NF-κB-dependent immediate-early genes via RelA Ser 276 phosphorylation coupled to CDK9 promoter recruitment. Nucleic Acids Res. 42, 8416–8432 (2014).
  CAS PubMed PubMed Central Google Scholar
• McNamara, R. P., McCann, J. L., Gudipaty, S. A. & D'Orso, I. Transcription factors mediate the enzymatic disassembly of promoter-bound 7SK snRNP to locally recruit P-TEFb for transcription elongation. Cell Rep. 5, 1256–1268 (2013).
  CAS PubMed Google Scholar
• Gilchrist, D. et al. Regulating the regulators: the pervasive effects of Pol II pausing on stimulus-responsive gene networks. Genes Dev. 26, 933–944 (2012).
  CAS PubMed PubMed Central Google Scholar
• Ji, X. et al. SR proteins collaborate with 7SK and promoter-associated nascent RNA to release paused polymerase. Cell 153, 855–868 (2013). This study implicates an RNA-binding protein that was traditionally thought to function in splicing in the regulated release of paused Pol II to productive elongation.
  CAS PubMed PubMed Central Google Scholar
• Barboric, M. et al. 7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development. Proc. Natl Acad. Sci. USA 106, 7798–7803 (2009).
  CAS PubMed PubMed Central Google Scholar
• Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
  CAS PubMed Google Scholar
• Whyte, W. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).
  CAS PubMed PubMed Central Google Scholar
• Brown, J. D. et al. NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol. Cell 56, 219–231 (2014).
  CAS PubMed PubMed Central Google Scholar
• Lai, F. et al. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature 494, 497–501 (2013).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Schaukowitch, K. et al. Enhancer RNA facilitates NELF release from immediate early genes. Mol. Cell 56, 29–42 (2014).
  CAS PubMed PubMed Central Google Scholar
• Schaaf, C. A. et al. Genome-wide control of RNA polymerase II activity by cohesin. PLoS Genet. 9, e1003382 (2013).
  CAS PubMed PubMed Central Google Scholar
• Thummel, C. S., Burtis, K. C. & Hogness, D. S. Spatial and temporal patterns of E74 transcription during Drosophila development. Cell 61, 101–111 (1990).
  CAS PubMed Google Scholar
• Heidemann, M., Hintermair, C., Voß, K. & Eick, D. Dynamic phosphorylation patterns of RNA polymerase II CTD during transcription. Biochim. Biophys. Acta 1829, 55–62 (2013).
  CAS PubMed Google Scholar
• Glover-Cutter, K., Kim, S., Espinosa, J. & Bentley, D. RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nature Struct. Mol. Biol. 15, 71–78 (2007).
  Google Scholar
• Martin, R., Rino, J., Carvalho, C., Kirchhausen, T. & Carmo-Fonseca, M. Live-cell visualization of pre-mRNA splicing with single-molecule sensitivity. Cell Rep. 4, 1144–1155 (2013).
  CAS PubMed PubMed Central Google Scholar
• Zentner, G. & Henikoff, S. Regulation of nucleosome dynamics by histone modifications. Nature Struct. Mol. Biol. 20, 259–266 (2013).
  CAS Google Scholar
• Bintu, L. et al. Nucleosomal elements that control the topography of the barrier to transcription. Cell 151, 738–749 (2012). In this study, optical tweezers were used to measure the movement of individual transcribing Pol II complexes through nucleosomes in real-time and thereby describes the energetic barriers in nucleosomes that could contribute to pausing.
  CAS PubMed PubMed Central Google Scholar
• Ardehali, M. B. et al. Spt6 enhances the elongation rate of RNA polymerase II in vivo. EMBO J. 28, 1067–1077 (2009).
  CAS PubMed PubMed Central Google Scholar
• Wu, L., Li, L., Zhou, B., Qin, Z. & Dou, Y. H2B ubiquitylation promotes RNA pol II processivity via PAF1 and pTEFb. Mol. Cell 54, 920–931 (2014).
  CAS PubMed PubMed Central Google Scholar
• Jung, I. et al. H2B monoubiquitylation is a 5′-enriched active transcription mark and correlates with exon-intron structure in human cells. Genome Res. 22, 1026–1035 (2012).
  CAS PubMed PubMed Central Google Scholar
• Shilatifard, A., Conaway, R. C. & Conaway, J. W. The RNA polymerase II elongation complex. Annu. Rev. Biochem. 72, 693–715 (2003).
  CAS PubMed Google Scholar
• Amit, M. et al. Differential GC content between exons and introns establishes distinct strategies of splice-site recognition. Cell Rep. 1, 543–556 (2012).
  CAS PubMed Google Scholar
• Tilgner, H. et al. Nucleosome positioning as a determinant of exon recognition. Nature Struct. Mol. Biol. 16, 996–1001 (2009).
  CAS Google Scholar
• Schwartz, S., Meshorer, E. & Ast, G. Chromatin organization marks exon-intron structure. Nature Struct. Mol. Biol. 16, 990–995 (2009).
  CAS Google Scholar
• Close, P. et al. DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation. Nature 484, 386–389 (2012).
  CAS PubMed PubMed Central Google Scholar
• Huff, J., Plocik, A., Guthrie, C. & Yamamoto, K. Reciprocal intronic and exonic histone modification regions in humans. Nature Struct. Mol. Biol. 17, 1495–1499 (2010).
  CAS Google Scholar
• Saint-André, V., Batsché, E., Rachez, C. & Muchardt, C. Histone H3 lysine 9 trimethylation and HP1γ favor inclusion of alternative exons. Nature Struct. Mol. Biol. 18, 337–344 (2011).
  Google Scholar
• Schor, I. E., Rascovan, N., Pelisch, F., Alló, M. & Kornblihtt, A. R. Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing. Proc. Natl Acad. Sci. USA 106, 4325–4330 (2009).
  CAS PubMed PubMed Central Google Scholar
• Ip, J. et al. Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation. Genome Res. 21, 390–401 (2011).
  CAS PubMed PubMed Central Google Scholar
• Hein, P. P. et al. RNA polymerase pausing and nascent-RNA structure formation are linked through clamp-domain movement. Nature Struct. Mol. Biol. 21, 794–802 (2014).
  CAS Google Scholar
• Skourti-Stathaki, K., Proudfoot, N. & Gromak, N. Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2- dependent termination. Mol. Cell 42, 794–805 (2011).
  CAS PubMed PubMed Central Google Scholar
• Ozer, A., Pagano, J. M. & Lis, J. T. New technologies provide quantum changes in the scale, speed, and success of SELEX methods and aptamer characterization. Mol. Ther. Nucleic Acids 3, e183 (2014).
  CAS PubMed PubMed Central Google Scholar
• Lee, T. I. & Young, R. A. Transcriptional regulation and its misregulation in disease. Cell 152, 1237–1251 (2013).
  CAS PubMed PubMed Central Google Scholar
• Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524–528 (2011).
  CAS PubMed PubMed Central Google Scholar
• Dawson, M. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533 (2011).
  CAS PubMed PubMed Central Google Scholar
• Singh, J. & Padgett, R. Rates of in situ transcription and splicing in large human genes. Nature Struct. Mol. Biol. 16, 1128–1133 (2009).
  CAS Google Scholar
• Churchman, L. & Weissman, J. Nascent transcript sequencing visualizes transcription at nucleotide resolution. Nature 469, 368–373 (2011).
  CAS PubMed Google Scholar
• Yao, J., Munson, K., Webb, W. & Lis, J. Dynamics of heat shock factor association with native gene loci in living cells. Nature 442, 1050–1053 (2006).
  CAS PubMed Google Scholar
• Boireau, S. et al. The transcriptional cycle of HIV-1 in real-time and live cells. J. Cell Biol. 179, 291–304 (2007).
  CAS PubMed PubMed Central Google Scholar
• Brody, Y. et al. The in vivo kinetics of RNA polymerase II elongation during co-transcriptional splicing. PLoS Biol. 9, e1000573 (2011).
  CAS PubMed PubMed Central Google Scholar
• Darzacq, X. et al. In vivo dynamics of RNA polymerase II transcription. Nature Struct. Mol. Biol. 14, 796–806 (2007).
  CAS Google Scholar
• Tennyson, C. N., Klamut, H. J. & Worton, R. G. The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced. Nature Genet. 9, 184–190 (1995).
  CAS PubMed Google Scholar
• Mason, P. & Struhl, K. Distinction & relationship between elongation rate & processivity of RNA polymerase II in vivo. Mol. Cell 17, 831–840 (2005).
  CAS PubMed Google Scholar
• Ameur, A. et al. Total RNA sequencing reveals nascent transcription and widespread co-transcriptional splicing in the human brain. Nature Struct. Mol. Biol. 18, 1435–1440 (2011).
  CAS Google Scholar