Transcription and chromatin function are regulated by proteins that bind to DNA, nucleosomes or RNA polymerase II, with specific non-coding RNAs (ncRNAs) functioning to modulate their recruitment or activity. Unlike ncRNAs, nascent pre-mRNA was considered to be primarily a passive player in these processes. In this Opinion article, we describe recently identified interactions between nascent pre-mRNAs and regulatory proteins, highlight commonalities between the functions of nascent pre-mRNA and nascent ncRNA, and propose that both types of RNA have an active role in transcription and chromatin regulation.
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Peterlin, B. M. & Price, D. H. Controlling the elongation phase of transcription with P-TEFb. Mol. Cell 23, 297–305 (2006).
Tsai, M. C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010).
Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).
Zhao, J., Sun, B. K., Erwin, J. A., Song, J. J. & Lee, J. T. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322, 750–756 (2008).
Pandey, R. R. et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol. Cell 32, 232–246 (2008).
Rinn, J. L. & Chang, H. Y. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145–166 (2012).
Kim, T.-K. & Shiekhattar, R. Diverse regulatory interactions of long noncoding RNAs. Curr. Opin. Genet. Dev. 36, 73–82 (2016).
Li, W., Notani, D. & Rosenfeld, M. G. Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat. Rev. Genet. 17, 207–223 (2016).
Lee, J. T. Epigenetic regulation by long noncoding RNAs. Science 338, 1435–1439 (2012).
Beltran, M. et al. The interaction of PRC2 with RNA or chromatin is mutually antagonistic. Genome Res. 26, 896–907 (2016).
Hendrickson, D. G., Kelley, D. R., Tenen, D., Bernstein, B. & Rinn, J. L. Widespread RNA binding by chromatin-associated proteins. Genome Biol. 17, 28 (2016).
Proudfoot, N. J. Transcriptional termination in mammals: stopping the RNA polymerase II juggernaut. Science 352, aad9926 (2016).
Santos-Pereira, J. M. & Aguilera, A. R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 16, 583–597 (2015).
Ji, X. et al. SR proteins collaborate with 7SK and promoter-associated nascent RNA to release paused polymerase. Cell 153, 855–868 (2013).
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).
Pagano, J. M. et al. Defining NELF-E RNA binding in HIV-1 and promoter-proximal pause regions. PLoS Genet. 10, e1004090 (2014).
Missra, A. & Gilmour, D. S. Interactions between DSIF (DRB sensitivity inducing factor), NELF (negative elongation factor), and the Drosophila RNA polymerase II transcription elongation complex. Proc. Natl Acad. Sci. USA 107, 11301–11306 (2010).
Saldi, T., Cortazar, M. A., Sheridan, R. M. & Bentley, D. L. Coupling of RNA polymerase II transcription elongation with pre-mRNA splicing. J. Mol. Biol. 428, 2623–2635 (2016).
Naftelberg, S., Schor, I. E., Ast, G. & Kornblihtt, A. R. Regulation of alternative splicing through coupling with transcription and chromatin structure. Annu. Rev. Biochem. 84, 165–198 (2015).
Custódio, N. & Carmo-Fonseca, M. Co-transcriptional splicing and the CTD code. Crit. Rev. Biochem. Mol. Biol. 51, 395–411 (2016).
Alexander, R. D., Innocente, S. A., Barrass, J. D. & Beggs, J. D. Splicing-dependent RNA polymerase pausing in yeast. Mol. Cell 40, 582–593 (2010).
Chathoth, K. T., Barrass, J. D., Webb, S. & Beggs, J. D. A splicing-dependent transcriptional checkpoint associated with prespliceosome formation. Mol. Cell 53, 779–790 (2014).
Nojima, T. et al. Mammalian NET-Seq reveals genome-wide nascent transcription coupled to RNA processing. Cell 161, 526–540 (2015).
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).
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).
Mayer, A. et al. Native elongating transcript sequencing reveals human transcriptional activity at nucleotide resolution. Cell 161, 541–554 (2015).
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).
de Almeida, S. F. et al. Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36. Nat. Struct. Mol. Biol. 18, 977–983 (2011).
Kim, S., Kim, H., Fong, N., Erickson, B. & Bentley, D. L. Pre-mRNA splicing is a determinant of histone H3K36 methylation. Proc. Natl Acad. Sci. USA 108, 13564–13569 (2011).
Convertini, P. et al. Sudemycin E influences alternative splicing and changes chromatin modifications. Nucleic Acids Res. 42, 4947–4961 (2014).
Yuan, W. et al. Heterogeneous nuclear ribonucleoprotein L Is a subunit of human KMT3a/Set2 complex required for H3 Lys-36 trimethylation activity in vivo. J. Biol. Chem. 284, 15701–15707 (2009).
Zhao, J. et al. Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol. Cell 40, 939–953 (2010).
Davidovich, C., Zheng, L., Goodrich, K. J. & Cech, T. R. Promiscuous RNA binding by Polycomb repressive complex 2. Nat. Struct. Mol. Biol. 20, 1250–1257 (2013).
Kaneko, S., Son, J., Shen, S. S., Reinberg, D. & Bonasio, R. PRC2 binds active promoters and contacts nascent RNAs in embryonic stem cells. Nat. Struct. Mol. Biol. 20, 1258–1264 (2013).
Kaneko, S., Son, J., Bonasio, R., Shen, S. S. & Reinberg, D. Nascent RNA interaction keeps PRC2 activity poised and in check. Genes Dev. 28, 1983–1988 (2014).
Davidovich, C. et al. Toward a consensus on the binding specificity and promiscuity of PRC2 for RNA. Mol. Cell 57, 552–558 (2015).
Riising, E. M. et al. Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide. Mol. Cell 55, 347–360 (2014).
Jermann, P., Hoerner, L., Burger, L. & Schubeler, D. Short sequences can efficiently recruit histone H3 lysine 27 trimethylation in the absence of enhancer activity and DNA methylation. Proc. Natl Acad. Sci. USA 111, 3415–3421 (2014).
Cifuentes-Rojas, C., Hernandez, A. J., Sarma, K. & Lee, J. T. Regulatory interactions between RNA and polycomb repressive complex 2. Mol. Cell 55, 171–185 (2014).
Herzog, V. A. et al. A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element. Nat. Genet. 46, 973–981 (2014).
Chen, P. B., Chen, H. V., Acharya, D., Rando, O. J. & Fazzio, T. G. R loops regulate promoter-proximal chromatin architecture and cellular differentiation. Nat. Struct. Mol. Biol. 22, 999–1007 (2015).
Wei, C. et al. RBFox2 binds nascent RNA to globally regulate Polycomb complex 2 targeting in mammalian genomes. Mol. Cell 62, 875–889 (2016).
Di Ruscio, A. et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 503, 371–376 (2013).
Holz-Schietinger, C. & Reich, N. O. RNA modulation of the human DNA methyltransferase 3A. Nucleic Acids Res. 40, 8550–8557 (2012).
Savell, K. E. et al. Extra-coding RNAs regulate neuronal DNA methylation dynamics. Nat. Commun. 7, 12091 (2016).
Tilgner, H. et al. Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs. Genome Res. 22, 1616–1625 (2012).
Fan, J. et al. Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. Genome Biol. 16, 139 (2015).
Wang, K. C. et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472, 120–124 (2011).
Lai, F. et al. Activating RNAs associate with mediator to enhance chromatin architecture and transcription. Nature 494, 497–501 (2013).
Li, W. et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498, 516–520 (2013).
Yang, L. et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 500, 598–602 (2013).
Yang, Y. W. et al. Essential role of lncRNA binding for WDR5 maintenance of active chromatin and embryonic stem cell pluripotency. eLife 3, e02046 (2014).
Jeon, Y. & Lee, J. T. YY1 tethers Xist RNA to the inactive X nucleation center. Cell 146, 119–133 (2011).
Sigova, A. A. et al. Transcription factor trapping by RNA in gene regulatory elements. Science 350, 978–981 (2015).
Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).
Engreitz, J. M. et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 539, 452–455 (2016).
Vance, K. W. & Ponting, C. P. Transcriptional regulatory functions of nuclear long noncoding RNAs. Trends Genet. 30, 348–355 (2014).
Nickerson, J. A., Krochmalnic, G., Wan, K. M. & Penman, S. Chromatin architecture and nuclear RNA. Proc. Natl Acad. Sci. USA 86, 177–181 (1989).
Hall, L. L. et al. Stable CoT-1 repeat RNA is abundant and associated with euchromatic interphase chromosomes. Cell 156, 907–919 (2014).
Cerase, A., Pintacuda, G., Tattermusch, A. & Avner, P. Xist localization and function: new insights from multiple levels. Genome Biol. 16, 166 (2015).
Phillips-Cremins, J. E. et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153, 1281–1295 (2013).
Kagey, M. H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010).
Kung, J. T. et al. Locus-specific targeting to the X chromosome revealed by the RNA interactome of CTCF. Mol. Cell 57, 361–375 (2015).
Saldaña-Meyer, R. et al. CTCF regulates the human p53 gene through direct interaction with its natural antisense transcript, Wrap53. Genes Dev. 28, 723–734 (2014).
Shevtsov, S. P. & Dundr, M. Nucleation of nuclear bodies by RNA. Nat. Cell Biol. 13, 167–173 (2011).
Ulveling, D., Francastel, C. & Hubé, F. When one is better than two: RNA with dual functions. Biochimie 93, 633–644 (2011).
Kole, R., Krainer, A. R. & Altman, S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat. Rev. Drug Discov. 11, 125–140 (2012).
O'Connell, M. R. et al. Programmable RNA recognition and cleavage by CRISPR/Cas9. Nature 516, 263–266 (2014).
Shechner, D. M., Hacisuleyman, E., Younger, S. T. & Rinn, J. L. Multiplexable, locus-specific targeting of long RNAs with CRISPR-Display. Nat. Methods 12, 664–670 (2015).
Frye, M., Jaffrey, S. R., Pan, T., Rechavi, G. & Suzuki, T. RNA modifications: what have we learned and where are we headed? Nat. Rev. Genet. 17, 365–372 (2016).
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).
Ginno, P. A., Lim, Y. W., Lott, P. L., Korf, I. & Chédin, 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).
Skourti-Stathaki, K., Kamieniarz-Gdula, K. & Proudfoot, N. J. R-Loops induce repressive chromatin marks over mammalian gene terminators. Nature 516, 436–439 (2014).
Castellano-Pozo, M. et al. R loops are linked to histone H3 S10 phosphorylation and chromatin condensation. Mol. Cell 52, 583–590 (2013).
Ginno, P. A., Lott, P. L., Christensen, H. C., Korf, I. & Chédin, F. R-Loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Mol. Cell 45, 814–825 (2012).
Boque-Sastre, R. et al. Head-to-head antisense transcription and R-loop formation promotes transcriptional activation. Proc. Natl Acad. Sci. USA 112, 5785–5790 (2015).
Sanz, L. et al. Prevalent, dynamic, and conserved R-loop structures associate with specific epigenomic signatures in mammals. Mol. Cell 63, 167–178 (2016).
Wang, X. et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454, 126–130 (2008).
Bose, D. A. et al. RNA binding to CBP stimulates histone acetylation and transcription. Cell 168, 135–149 (2017).
Zhao, D. Y. et al. SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination. Nature 529, 48–53 (2016).
Hatchi, E. et al. BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol. Cell 57, 636–647 (2015).
The authors are grateful to J. Rinn for his comments on the manuscript.
The authors declare no competing financial interests.
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Skalska, L., Beltran-Nebot, M., Ule, J. et al. Regulatory feedback from nascent RNA to chromatin and transcription. Nat Rev Mol Cell Biol 18, 331–337 (2017). https://doi.org/10.1038/nrm.2017.12
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