Skip to main content

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

  • Review Article
  • Published:

Modes of transcriptional regulation

Molecular mechanisms driving transcriptional stress responses

Nature Reviews Genetics volume 19, pages 385–397 (2018)Cite this article

Subjects

Abstract

Proteotoxic stress, that is, stress caused by protein misfolding and aggregation, triggers the rapid and global reprogramming of transcription at genes and enhancers. Genome-wide assays that track transcriptionally engaged RNA polymerase II (Pol II) at nucleotide resolution have provided key insights into the underlying molecular mechanisms that regulate transcriptional responses to stress. In addition, recent kinetic analyses of transcriptional control under heat stress have shown how cells ‘prewire’ and rapidly execute genome-wide changes in transcription while concurrently becoming poised for recovery. The regulation of Pol II at genes and enhancers in response to heat stress is coupled to chromatin modification and compartmentalization, as well as to co-transcriptional RNA processing. These mechanistic features seem to apply broadly to other coordinated genome-regulatory responses.

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

Fig. 1: Sensing, communicating and transcriptionally responding to protein-damaging stress.
Fig. 2: Heat shock response triggers transcriptional reprogramming of genes and enhancers across the genome.
Fig. 3: Promoter opening, establishment of directionality and rapid release of paused RNA polymerase II.
Fig. 4: Redistribution of transcription machinery upon heat shock.
Fig. 5: Co-transcriptional processing in heat-stressed cells.

Similar content being viewed by others

References

  1. Richter, K., Haslbeck, M. & Buchner, J. The heat shock response: life on the verge of death. Mol. Cell 40, 253–266 (2010).

    Article  PubMed  CAS  Google Scholar 

  2. Toivola, D. M., Strnad, P., Habtezion, A. & Omary, M. B. Intermediate filaments take the heat as stress proteins. Trends. Cell. Biol. 20, 79–91 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).

    Article  PubMed  CAS  Google Scholar 

  4. Quirós, P. M., Langer, T. & López-Otín, C. New roles for mitochondrial proteases in health, ageing and disease. Nat. Rev. Mol. Cell Biol. 16, 345–359 (2015).

    Article  PubMed  CAS  Google Scholar 

  5. Majmundar, A. J., Wong, W. J. & Simon, M. C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 40, 294–309 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Gomez-Pastor, R., Burchfiel, E. T. & Thiele, D. J. Regulation of heat shock transcription factors and their roles in physiology and disease. Nat. Rev. Mol. Cell Biol. 19, 4–19 (2018).

    Article  PubMed  CAS  Google Scholar 

  7. Gidalevitz, T., Prahlad, V. & Morimoto, R. I. The stress of protein misfolding: from single cells to multicellular organisms. Cold Spring Harb. Perspect. Biol. 3, a009704 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Vihervaara, A. & Sistonen, L. HSF1 at a glance. J. Cell. Sci. 127, 261–266 (2014).

    Article  PubMed  CAS  Google Scholar 

  9. Duarte, F. M. et al. Transcription factors GAF and HSF act at distinct regulatory steps to modulate stress-induced gene activation. Genes Dev. 30, 1731–1746 (2016). This study demonstrates that pausing is an indispensable step for heat-induced transcription and maps the global transcriptional changes in heat-stressed Drosophila cells.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Mahat, D. B., Salamanca, H. H., Duarte, F. M., Danko, C. G. & Lis, J. T. Mammalian heat shock response and mechanisms underlying its genome-wide transcriptional regulation. Mol. Cell 62, 63–78 (2016). This paper maps detailed kinetics of nascent transcription in heat-stressed mouse cells.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Vihervaara, A. et al. Transcriptional response to stress is pre-wired by promoter and enhancer architecture. Nat. Commun. 8, 255 (2017). This report quantifies transcriptional changes at nucleotide resolution across genes and enhancers in human cells, identifying mechanisms that establish directionality and prewire transactivation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Guertin, M. J., Petesch, S. J., Zobeck, K. L., Min, I. M. & Lis, J. T. Drosophila heat shock system as a general model to investigate transcriptional regulation. Cold Spring Harb. Symp. Quant. Biol. 75, 1–9 (2010).

    Article  PubMed  CAS  Google Scholar 

  13. Prostko, C. R., Brostrom, M. A. & Brostrom, C. O. Reversible phosphorylation of eukaryotic initiation factor 2 alpha in response to endoplasmic reticular signaling. Mol. Cell. Biochem. 127–128, 255–265 (1993).

    Article  PubMed  Google Scholar 

  14. Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H. & Ron, D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell 5, 897–904 (2000).

    Article  PubMed  CAS  Google Scholar 

  15. Gebauer, F. & Hentze, M. W. Molecular mechanisms of translational control. Nat. Rev. Mol. Cell Biol. 5, 827–835 (2004).

    Article  PubMed  CAS  Google Scholar 

  16. Prahlad, V., Cornelius, T. & Morimoto, R. I. Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons. Science 320, 811–814 (2008). This study identifies organismal control over cellular stress responses in C. elegans.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. van Oosten-Hawle, P., Porter, R. S. & Morimoto, R. I. Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 153, 1366–1378 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Katayama, T. et al. Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat. Cell. Biol. 1, 479–485 (1999).

    Article  PubMed  CAS  Google Scholar 

  19. Yoo, B. C., Kim, S. H., Cairns, N., Fountoulakis, M. & Lubec, G. Deranged expression of molecular chaperones in brains of patients with Alzheimer’s disease. Biochem. Biophys. Res. Commun. 280, 249–258 (2001).

    Article  PubMed  CAS  Google Scholar 

  20. Dai, C., Whitesell, L., Rogers, A. B. & Lindquist, S. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130, 1005–1018 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Mendillo, M. L. et al. HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell 150, 549–562 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Gomez-Pastor, R. et al. Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease. Nat. Commun. 8, 14405 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Sannino, S. & Brodsky, J. L. Targeting protein quality control pathways in breast cancer. BMC. Biol. 15, 109 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ritossa, F. M. A new puffing pattern induced by a temperature shock and DNP in Drosophila. Experientia 18, 571–573 (1962).

    Article  CAS  Google Scholar 

  25. Tissières, A., Mitchell, H. K. & Tracy, U. M. Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J. Mol. Biol. 84, 389–398 (1974).

    Article  PubMed  Google Scholar 

  26. DiDomenico, B. J., Bugaisky, G. E. & Lindquist, S. Heat shock and recovery are mediated by different translational mechanisms. Proc. Natl. Acad. Sci. USA 79, 6181–6185 (1982).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Niskanen, E. A. et al. Global SUMOylation on active chromatin is an acute heat stress response restricting transcription. Genome Biol. 16, 153 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Dukler Booth, G. et al. Nascent RNA sequencing reveals a dynamic global transcriptional response at genes and enhancers to the natural medicinal compound celastrol. Genome Res. 27, 1816–1829 (2017).

    Article  PubMed  CAS  Google Scholar 

  29. Mueller, B. et al. Widespread changes in nucleosome accessibility without changes in nucleosome occupancy during a rapid transcriptional induction. Genes Dev. 31, 451–462 (2017). This paper shows globally increased chromatin accessibility and nucleosome remodelling at stress-induced genes.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Hahn, J. S., Hu, Z., Thiele, D. J. & Iyer, V. R. Genome-wide analysis of the biology of stress responses through heat shock transcription factor. Mol. Cell. Biol. 24, 5249–5256 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Vihervaara, A. et al. Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells. Proc. Natl. Acad. Sci. USA 110, E3388–E3397 (2013). This study maps HSF1 and HSF2 target loci in freely cycling and mitotic human cells, demonstrating how HSF2 marks genes for post-mitotic transcription whereas HSF1 is largely excluded from the dividing chromatin.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Guertin, M. J., & Lis, J. T. Chromatin landscape dictates HSF binding to target DNA elements. PLoS Genet. 6, e1001114 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Fuda, N. J., Ardehali, M. B. & Lis, J. T. Defining mechanisms that regulate RNA polymerase II transcription in vivo. Nature 461, 186–192 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Adelman, K. & Lis, J. T. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat. Rev. Genet. 13, 720–731 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Core, L. J. et al. Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nat. Genet. 46, 1311–1320 (2014). Identifies enhancers across the genome by their divergent pattern of transcription that produces unstable transcripts to both directions.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 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 report describes the development of global run-on sequencing methodology and the identification of divergent transcription from genes.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 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, the authors refine global run-on sequencing to nucleotide resolution and identify mechanisms that coordinate initiation and pausing.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Gasch, A. P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Murray, J. I. et al. Diverse and specific gene expression responses to stresses in cultured human cells. Mol. Biol. Cell 15, 2361–2374 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Trinklein, N. D., Murray, J. I., Hartman, S. J., Botstein, D. & Myers, R. M. The role of heat shock transcription factor 1 in the genome-wide regulation of the mammalian heat shock response. Mol. Biol. Cell 15, 1254–1261 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Sorensen, J. G., Nielsen, M. M., Kruhoffer, M., Justesen, J. & Loeschcke, V. Full genome gene expression analysis of the heat stress response in Drosophila melanogaster. Cell Stress Chaperones 10, 312–328 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. López-Maury, L., Marguerat, S. & Bähler, J. Tuning gene expression to changing environments: from rapid responses to evolutionary adaptation. Nat. Rev. Genet. 9, 583–593 (2008).

    Article  PubMed  CAS  Google Scholar 

  44. Yao, J., Munson, K. M., Webb, W. W. & Lis, J. T. Dynamics of heat shock factor association with native gene loci in living cells. Nature 442, 1050–1053 (2006).

    Article  PubMed  CAS  Google Scholar 

  45. Yao, J., Ardehali, M. B., Fecko, C. J., Webb, W. W. & Lis, J. T. Intranuclear distribution and local dynamics of RNA polymerase II during transcription activation. Mol. Cell 28, 978–990 (2007).

    Article  PubMed  CAS  Google Scholar 

  46. Yao, J., Zobeck, K. L., Lis, J. T. & Webb, W. W. Imaging transcription dynamics at endogenous genes in living Drosophila tissues. Methods 45, 233–241 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Zobeck, K. L., Buckley, M. S., Zipfel, W. R. & Lis, J. T. Recruitment timing and dynamics of transcription factors at the Hsp70 loci in living cells. Mol. Cell 40, 965–975 (2010). This paper represents a detailed identification of the kinetic events that mediate transactivation of the Drosophila Hsp70 gene.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Teves, S. S. & Henikoff, S. Heat shock reduces stalled RNA polymerase II and nucleosome turnover genome-wide. Genes Dev. 25, 2387–2397 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Lai, W. K. & Pugh, B. F. Genome-wide uniformity of human ‘open’ pre-initiation complexes. Genome Res. 27, 15–26 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Fuda, N. J. et al. GAGA factor maintains nucleosome-free regions and has a role in RNA polymerase II recruitment to promoters. PLoS Genet. 11, e1005108 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Xiao, H. et al. Dual functions of largest NURF subunit NURF301 in nucleosome sliding and transcription factor interactions. Mol. Cell 8, 531–543 (2001).

    Article  PubMed  CAS  Google Scholar 

  53. Tsukiyama, T. & Wu, C. Purification and properties of an ATP-dependent nucleosome remodeling factor. Cell 83, 1011–1020 (1995).

    Article  PubMed  CAS  Google Scholar 

  54. Badenhorst, P. et al. The Drosophila nucleosome remodeling factor NURF is required for Ecdysteroid signaling and metamorphosis. Genes. Dev. 19, 2540–2545 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Fujimoto, M. et al. RPA assists HSF1 access to nucleosomal DNA by recruiting histone chaperone FACT. Mol. Cell 48, 182–194 (2012).

    Article  PubMed  CAS  Google Scholar 

  56. Andersson, R. et al. Human gene promoters are intrinsically bidirectional. Mol. Cell 60, 346–347 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Scruggs, B. S. et al. Bidirectional transcription arises from two distinct hubs of transcription factor binding and active chromatin. Mol. Cell 58, 1101–1112 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Pugh, B. F. & Venters, B. J. Genomic organization of human transcription initiation complexes. PLoS ONE 11, 0149339 (2016).

    Google Scholar 

  59. He, Q., Johnston, J. & Zeitlinger, J. ChIP-nexus enables improved detection of in vivo transcription factor binding footprints. Nat. Biotechnol. 33, 395–401 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Rougvie, A. E. & Lis, J. T. The RNA polymerase II molecule at the 5ʹ end of the uninduced hsp70 gene of D. melanogaster is transcriptionally engaged. Cell 54, 795–804 (1988). This study identifies promoter-proximal pausing of Pol II by showing that the Pol II complex that resides 20-50 nucleotides downstream of the TSS is transcriptionally engaged.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. 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 

  63. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Topol, J., Ruden, D. M. & Parker, C. S. Sequences required for in vitro transcriptional activation of a Drosophila hsp70 gene. Cell 42, 527–537 (1985).

    Article  PubMed  CAS  Google Scholar 

  66. Wiederrecht, G., Shuey, D. J., Kibbe, W. A. & Parker, C. S. The Saccharomyces and Drosophila heat shock transcription factors are identical in size and DNA binding properties. Cell 48, 507–515 (1987).

    Article  PubMed  CAS  Google Scholar 

  67. Wu, C. et al. Purification and properties of Drosophila heat shock activator protein. Science 238, 1247–1253 (1987).

    Article  PubMed  CAS  Google Scholar 

  68. Åkerfelt, M. et al. Heat shock transcription factor 1 localizes to sex chromatin during meiotic repression. J. Biol. Chem. 285, 34469–34476 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Elsing, A. N. et al. Expression of HSF2 decreases in mitosis to enable stress-inducible transcription and cell survival. J. Cell Biol. 206, 735–749 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Sullivan, E. K., Weirich, C. S., Guyon, J. R., Sif, S. & Kingston, R. E. Transcriptional activation domains of human heat shock factor 1 recruit human SWI/SNF. Mol. Cell. Biol. 21, 5826–5837 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Petesch, S. J. & Lis, J. T. Activator-induced spread of poly(ADP-ribose) polymerase promotes nucleosome loss at Hsp70. Mol. Cell 45, 64–74 (2012).

    Article  PubMed  CAS  Google Scholar 

  72. Corey, L. L., Weirich, C. S., Benjamin, I. J. & Kingston, R. E. Localized recruitment of a chromatin-remodeling activity by an activator in vivo drives transcriptional elongation. Genes. Dev. 17, 1392–1401 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Thomson, S., Hollis, A., Hazzalin, C. A. & Mahadevan, L. C. Distinct stimulus-specific histone modifications at hsp70 chromatin targeted by the transcription factor heat shock factor-1. Mol. Cell 15, 585–594 (2004).

    Article  PubMed  CAS  Google Scholar 

  74. Solís, E. J. et al. Defining the essential function of yeast Hsf1 reveals a compact transcriptional program for maintaining eukaryotic proteostasis. Mol. Cell 63, 60–71 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Lis, J. T., Mason, P., Peng, J., Price, D. H. & Werner, J. P-TEFb kinase recruitment and function at heat shock loci. Genes Dev. 14, 792–803 (2000).

    PubMed  PubMed Central  CAS  Google Scholar 

  76. Jonkers, I. & Lis, J. T. Getting up to speed with transcription elongation by RNA polymerase II. Nat. Rev. Mol. Cell Biol. 16, 167–177 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Shao, W. & Zeitlinger, J. Paused RNA polymerase II inhibits new transcriptional initiation. Nat. Genet. 49, 1045–1051 (2017).

    Article  PubMed  CAS  Google Scholar 

  78. Gressel, S. et al. CDK9-dependent RNA polymerase II pausing controls transcription initiation. eLife 6, e29736 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Banerji, J., Rusconi, S. & Schaffner, W. Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell 27, 299–308 (1981).

    Article  PubMed  CAS  Google Scholar 

  80. Buecker, C. & Wysocka, J. Enhancers as information integration hubs in development: lessons from genomics. Trends Genet. 28, 276–284 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Long, H. K., Prescott, S. L. & Wysocka, J. Ever-changing landscapes: transcriptional enhancers in development and evolution. Cell 167, 1170–1187 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Henriques, T. et al. Widespread transcriptional pausing and elongation control at enhancers. Genes Dev. 32, 26–41 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  85. Mikhaylichenko, O. et al. The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription. Genes Dev. https://doi.org/10.1101/gad.308619.117 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Arner, E. et al. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science 347, 1010–1014 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Bradner, J. E., Hnisz, D. & Young, R. A. Transcriptional addiction in cancer. Cell 168, 629–643 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Chen, F. X. et al. PAF1 regulation of promoter-proximal pause release via enhancer activation. Science 357, 1294–1298 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  90. Dekker, J. & Misteli, T. Long-range chromatin interactions. Cold Spring Harb. Perspect. Biol. 7, a019356 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Chowdhary, S., Kainth, A. S. & Gross, D. S. Heat shock protein genes undergo dynamic alteration in their three-dimensional structure and genome organization in response to thermal stress. Mol. Cell. Biol. 37, e00292-17 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Li, L. et al. Widespread rearrangement of 3D chromatin organization underlies polycomb-mediated stress-induced silencing. Mol. Cell 58, 216–231 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Galvani, A. & Thiriet, C. Nucleosome dancing at the tempo of histone tail acetylation. Genes 6, 607–621 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Splinter, E. et al. CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. Genes Dev. 20, 2349–2354 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Guo, Y. CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice. Proc. Natl. Acad. Sci. USA 109, 21081–21086 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Weintraub, A. S. et al. YY1 is a structural regulator of enhancer-promoter loops. Cell 171, 1573–1588 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  97. Bai, P. Biology of poly(ADP-ribose) polymerases: the factotums of cell maintenance. Mol. Cell 58, 947–958 (2015).

    Article  PubMed  CAS  Google Scholar 

  98. Niskanen, E. A. & Palvimo, J. J. Chromatin SUMOylation in heat stress: to protect, pause and organise? SUMO stress response on chromatin. Bioessays 39, 1600263 (2017).

    Article  CAS  Google Scholar 

  99. Haddad, N., Jost, D. & Vaillant, C. Perspectives: using polymer modeling to understand the formation and function of nuclear compartments. Chromosome Res. 25, 35–50 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Tulin, A. & Spradling, A. Chromatin loosening by poly(ADP)-ribose polymerase (PARP) at Drosophila puff loci. Science 299, 560–562 (2003).

    Article  PubMed  CAS  Google Scholar 

  101. Schreiber, V., Dantzer, F., & Ame, J. C. & de Murcia, G. Poly(ADP-ribose): novel functions for an old molecule. Nat. Rev. Mol. Cell Biol. 7, 517–528 (2006).

    Article  PubMed  CAS  Google Scholar 

  102. Martin, N. et al. PARP-1 transcriptional activity is regulated by sumoylation upon heat shock. EMBO J. 28, 3534–3548 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Ouararhni, K. et al. The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity. Genes Dev 20, 3324–3336 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Fujimoto, M. et al. The HSF1-PARP13-PARP1 complex facilitates DNA repair and promotes mammary tumorigenesis. Nat. Commun. 8, 1638 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Verger, A., Perdomo, J. & Crossley, M. Modification with SUMO. A role in transcriptional regulation. EMBO Rep. 4, 137–142 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Guo, C. & Henley, J. M. Wrestling with stress: roles of protein SUMOylation and deSUMOylation in cell stress response. IUBMB Life 66, 71–77 (2014).

    Article  PubMed  CAS  Google Scholar 

  107. Saitoh, H. & Hinchey, J. Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J. Biol. Chem. 275, 6252–6258 (2000).

    Article  PubMed  CAS  Google Scholar 

  108. Blomster, H. A. et al. Novel proteomics strategy brings insight into the prevalence of SUMO-2 target sites. Mol. Cell Proteom. 8, 1382–1390 (2009).

    Article  CAS  Google Scholar 

  109. Pellegrino, S. & Altmeyer, M. Interplay between ubiquitin, SUMO, and poly(ADP-ribose) in the cellular response to genotoxic stress. Front. Genet. 7, 63 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Fukuto, A. et al. SUMO modification system facilitates the exchange of histone variant H2A. Z-2 at DNA damage sites. Nucleus 9, 87–94 (2018).

    Article  PubMed  CAS  Google Scholar 

  111. Hnisz, D., Shrinivas, K., Young, R. A., Chakraborty, A. K. & Sharp, P. A. A phase separation model for transcriptional control. Cell 169, 13–23 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  113. Tippens, N. D., Vihervaara, A. & Lis, J. T. Enhancer transcription: what, where, when, and why? Genes Dev. 32, 1–3 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  114. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Shin, C., Feng, Y. & Manley, J. L. Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature 427, 553–558 (2004).

    Article  PubMed  CAS  Google Scholar 

  116. Di Giammartino, D. C., Shi, Y. & Manley, J. L. PARP1 represses PAP and inhibits polyadenylation during heat shock. Mol. Cell 49, 7–17 (2013). Identifies parylation of PAP and shows how its regulation defines polyadenylation in heat-stressed cells.

    Article  PubMed  CAS  Google Scholar 

  117. Shalgi, R., Hurt, J. A., Lindquist, S. & Burge, C. B. Widespread inhibition of posttranscriptional splicing shapes the cellular transcriptome following heat shock. Cell Rep. 7, 1362–1370 (2014). The authors measure co-transcriptional splicing across the transcriptome in stressed and unstressed mouse cells.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Vilborg, A. Comparative analysis reveals genomic features of stress-induced transcriptional readthrough. Proc. Natl. Acad. Sci. USA 114, E8362–E8371 (2017). This paper describes global read-through transcription upon osmotic, oxidative or heat stress.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Grosso, A. R. et al. Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma. eLife 4, e09214 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Rutkowski, A. J. et al. Widespread disruption of host transcription termination in HSV-1 infection. Nat. Commun. 6, 7126 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Vilborg, A., Passarelli, M. C., Yario, T. A., Tycowski, K. T. & Steitz, J. A. Widespread inducible transcription downstream of human genes. Mol. Cell 59, 449–461 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Ooi, F. K. & Prahlad, V. Olfactory experience primes the heat shock transcription factor HSF-1 to enhance the expression of molecular chaperones in C. elegans. Sci. Signal. 10, eaan4893 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Adamson, B. et al. A multiplexed single-cell CRISPR screening platform enables systematic dissection of the unfolded protein response. Cell 167, 1867–1882 (2016). This study identifies transcriptional responses mediated by the three UPR ER signalling pathways and demonstrates that cellular stress responses can be executed differently in distinct cells of a seemingly homogeneous population.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Liu, B., Chen, P., Xi, D., Zhu, H. & Gao, Y. ATF4 regulates CCL2 expression to promote endometrial cancer growth by controlling macrophage infiltration. Exp. Cell Res. 360, 105–112 (2017).

    Article  PubMed  CAS  Google Scholar 

  126. Acosta-Alvear, D. et al. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol. Cell 27, 53–66 (2007).

    Article  PubMed  CAS  Google Scholar 

  127. Fiorese, C. J. et al. The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr. Biol. 26, 2037–2043 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Zhao, Q. et al. A mitochondrial specific stress response in mammalian cells. EMBO J. 21, 4411–4419 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors apologize to their many colleagues whose important work was only indirectly cited. This work was financially supported by The Sigrid Jusélius Foundation (A.V.) and the National Institutes of Health (NIH) grant RO1-GM25232 (J.T.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA

    Anniina Vihervaara, Fabiana M. Duarte & John T. Lis

Authors
  1. Anniina Vihervaara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabiana M. Duarte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John T. Lis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article and reviewed or edited the manuscript before submission. A.V. and J.T.L. substantially contributed to discussions of the content and wrote the article.

Corresponding author

Correspondence to John T. Lis.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Unfolded protein response

(UPR). A cellular response that is triggered upon sensing of the accumulation of misfolded proteins.

Chaperones

Proteins that assist in folding, unfolding, assembly and disassembly of macromolecular structures.

Promoters

Regions, including the core promoter and upstream sequences (usually 1 kb or less), that contain binding sites for transcription factors and coordinate the expression of the downstream gene. At genes with divergent transcription, the promoter includes the region between the two core promoters.

Enhancers

Regions distal to gene promoters that have the potential to activate one or several genes.

Precision run-on sequencing

(PRO-seq). A method that maps the exact locations, orientation and amounts of transcribing RNA polymerases across the genome.

Celastrol

Chemical compound (pentacyclic triterpenoid) that induces the heat shock response and unfolded protein response and exhibits anti-inflammatory, anticancer and antioxidant activities.

Divergent transcription

A widespread phenomenon in various species in which active genes and enhancers are transcribed in both directions. At genes, the coding strand (sense direction) encodes a stable mRNA, whereas the non-protein-coding antisense transcripts are short and unstable. At enhancers, the transcripts, called enhancer RNAs (eRNAs), in both directions are short and unstable.

Core promoters

Short (~ 50 nucleotide) regions surrounding the transcription start site that provide a binding platform for general transcription factors (GTFs) and direct RNA polymerase II to initiation sites.

Promoter architecture

Positioning and dynamics of nucleosomes, chromatin remodellers, transcriptional regulators, the pre-initiation complex and transcriptionally engaged RNA polymerase II at the promoter.

Core initiation regions

Similar to core promoters, these regions are the sites of RNA polymerase II assembly and transcription initiation at promoters or enhancers.

Parylation

Post-translational modification of a single molecule, or chains of poly ADP-ribose, that are covalently attached to the catalytic enzyme (poly(ADP-ribose) polymerase 1 (PARP1)) itself or other proteins.

Sumoylation

Post-translational modification, whereby small ubiquitin-like modifier (SUMO) is covalently attached.

Phase separation

Formation of multimolecular, membrane-less assemblies that can compartmentalize biochemical reactions.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vihervaara, A., Duarte, F.M. & Lis, J.T. Molecular mechanisms driving transcriptional stress responses. Nat Rev Genet 19, 385–397 (2018). https://doi.org/10.1038/s41576-018-0001-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41576-018-0001-6

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