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.

  • Opinion
  • Published:

Regulatory feedback from nascent RNA to chromatin and transcription

Nature Reviews Molecular Cell Biology volume 18, pages 331–337 (2017)Cite this article

Subjects

An Author Correction to this article was published on 10 September 2019

This article has been updated

Abstract

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.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Nascent RNA couples RNA processing with transcription elongation and chromatin modification at specific positions along the gene.
Figure 2: Nascent RNA modulates the association of regulatory factors with chromatin to maintain gene activity.
Figure 3: Functional similarities between pre-mRNA and nascent ncRNAs and the formation of higher-order chromatin structures.

Similar content being viewed by others

Change history

  • 09 March 2017

    In the version of the article originally published online, an incorrect sentence in the legend of Figure 1 has now been corrected. The statement now reads: "The methyltransferase KMT3A is recruited to specific locations within the gene through mechanisms dependent on splicing and interactions with heterogeneous nuclear RNP L (HNRNPL), contributing to the enrichment of histone H3 Lys36 trimethylation (H3K36me3) at exons." In addition, the configuration of arrows in Figure 3b was incorrect. This has now been corrected.

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Tsai, M. C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pandey, R. R. et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol. Cell 32, 232–246 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Rinn, J. L. & Chang, H. Y. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145–166 (2012).

    CAS  PubMed  Google Scholar 

  7. Kim, T.-K. & Shiekhattar, R. Diverse regulatory interactions of long noncoding RNAs. Curr. Opin. Genet. Dev. 36, 73–82 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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).

    Article  CAS  PubMed  Google Scholar 

  9. Lee, J. T. Epigenetic regulation by long noncoding RNAs. Science 338, 1435–1439 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Beltran, M. et al. The interaction of PRC2 with RNA or chromatin is mutually antagonistic. Genome Res. 26, 896–907 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. Proudfoot, N. J. Transcriptional termination in mammals: stopping the RNA polymerase II juggernaut. Science 352, aad9926 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Santos-Pereira, J. M. & Aguilera, A. R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 16, 583–597 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pagano, J. M. et al. Defining NELF-E RNA binding in HIV-1 and promoter-proximal pause regions. PLoS Genet. 10, e1004090 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. Custódio, N. & Carmo-Fonseca, M. Co-transcriptional splicing and the CTD code. Crit. Rev. Biochem. Mol. Biol. 51, 395–411 (2016).

    Article  PubMed  CAS  Google Scholar 

  21. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nojima, T. et al. Mammalian NET-Seq reveals genome-wide nascent transcription coupled to RNA processing. Cell 161, 526–540 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mayer, A. et al. Native elongating transcript sequencing reveals human transcriptional activity at nucleotide resolution. Cell 161, 541–554 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  PubMed  CAS  Google Scholar 

  29. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Convertini, P. et al. Sudemycin E influences alternative splicing and changes chromatin modifications. Nucleic Acids Res. 42, 4947–4961 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhao, J. et al. Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol. Cell 40, 939–953 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Davidovich, C. et al. Toward a consensus on the binding specificity and promiscuity of PRC2 for RNA. Mol. Cell 57, 552–558 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Riising, E. M. et al. Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide. Mol. Cell 55, 347–360 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wei, C. et al. RBFox2 binds nascent RNA to globally regulate Polycomb complex 2 targeting in mammalian genomes. Mol. Cell 62, 875–889 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Di Ruscio, A. et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 503, 371–376 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Holz-Schietinger, C. & Reich, N. O. RNA modulation of the human DNA methyltransferase 3A. Nucleic Acids Res. 40, 8550–8557 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Savell, K. E. et al. Extra-coding RNAs regulate neuronal DNA methylation dynamics. Nat. Commun. 7, 12091 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  46. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fan, J. et al. Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. Genome Biol. 16, 139 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Wang, K. C. et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472, 120–124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lai, F. et al. Activating RNAs associate with mediator to enhance chromatin architecture and transcription. Nature 494, 497–501 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li, W. et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498, 516–520 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yang, L. et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 500, 598–602 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Jeon, Y. & Lee, J. T. YY1 tethers Xist RNA to the inactive X nucleation center. Cell 146, 119–133 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sigova, A. A. et al. Transcription factor trapping by RNA in gene regulatory elements. Science 350, 978–981 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Engreitz, J. M. et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 539, 452–455 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vance, K. W. & Ponting, C. P. Transcriptional regulatory functions of nuclear long noncoding RNAs. Trends Genet. 30, 348–355 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nickerson, J. A., Krochmalnic, G., Wan, K. M. & Penman, S. Chromatin architecture and nuclear RNA. Proc. Natl Acad. Sci. USA 86, 177–181 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hall, L. L. et al. Stable CoT-1 repeat RNA is abundant and associated with euchromatic interphase chromosomes. Cell 156, 907–919 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cerase, A., Pintacuda, G., Tattermusch, A. & Avner, P. Xist localization and function: new insights from multiple levels. Genome Biol. 16, 166 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Shevtsov, S. P. & Dundr, M. Nucleation of nuclear bodies by RNA. Nat. Cell Biol. 13, 167–173 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Ulveling, D., Francastel, C. & Hubé, F. When one is better than two: RNA with dual functions. Biochimie 93, 633–644 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Kole, R., Krainer, A. R. & Altman, S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat. Rev. Drug Discov. 11, 125–140 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. O'Connell, M. R. et al. Programmable RNA recognition and cleavage by CRISPR/Cas9. Nature 516, 263–266 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 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).

    Article  CAS  PubMed  Google Scholar 

  71. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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 

  74. Castellano-Pozo, M. et al. R loops are linked to histone H3 S10 phosphorylation and chromatin condensation. Mol. Cell 52, 583–590 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wang, X. et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454, 126–130 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bose, D. A. et al. RNA binding to CBP stimulates histone acetylation and transcription. Cell 168, 135–149 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  81. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are grateful to J. Rinn for his comments on the manuscript.

Author information

Authors and Affiliations

  1. Lenka Skalska, Manuel Beltran-Nebot and Richard G. Jenner are at the UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.,

    Lenka Skalska, Manuel Beltran-Nebot & Richard G. Jenner

  2. Jernej Ule is at the Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK,

    Jernej Ule

  3. The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.,

    Jernej Ule

Authors
  1. Lenka Skalska
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manuel Beltran-Nebot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jernej Ule
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard G. Jenner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jernej Ule or Richard G. Jenner.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (box)

Roles of non-coding RNAs in regulating transcription and chromatin function. (PDF 171 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2017.12

This article is cited by

Search

Advanced 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