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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Richter, K., Haslbeck, M. & Buchner, J. The heat shock response: life on the verge of death. Mol. Cell 40, 253–266 (2010).
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).
Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).
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).
Majmundar, A. J., Wong, W. J. & Simon, M. C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 40, 294–309 (2010).
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).
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).
Vihervaara, A. & Sistonen, L. HSF1 at a glance. J. Cell. Sci. 127, 261–266 (2014).
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.
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.
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.
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).
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).
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).
Gebauer, F. & Hentze, M. W. Molecular mechanisms of translational control. Nat. Rev. Mol. Cell Biol. 5, 827–835 (2004).
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.
van Oosten-Hawle, P., Porter, R. S. & Morimoto, R. I. Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 153, 1366–1378 (2013).
Katayama, T. et al. Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat. Cell. Biol. 1, 479–485 (1999).
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).
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).
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).
Gomez-Pastor, R. et al. Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease. Nat. Commun. 8, 14405 (2017).
Sannino, S. & Brodsky, J. L. Targeting protein quality control pathways in breast cancer. BMC. Biol. 15, 109 (2017).
Ritossa, F. M. A new puffing pattern induced by a temperature shock and DNP in Drosophila. Experientia 18, 571–573 (1962).
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).
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).
Niskanen, E. A. et al. Global SUMOylation on active chromatin is an acute heat stress response restricting transcription. Genome Biol. 16, 153 (2015).
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).
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.
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).
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.
Guertin, M. J., & Lis, J. T. Chromatin landscape dictates HSF binding to target DNA elements. PLoS Genet. 6, e1001114 (2010).
Fuda, N. J., Ardehali, M. B. & Lis, J. T. Defining mechanisms that regulate RNA polymerase II transcription in vivo. Nature 461, 186–192 (2009).
Adelman, K. & Lis, J. T. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat. Rev. Genet. 13, 720–731 (2012).
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.
Core, L. J. et al. Defining the status of RNA polymerase at promoters. Cell Rep. 2, 1025–1035 (2012).
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.
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.
Gasch, A. P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000).
Murray, J. I. et al. Diverse and specific gene expression responses to stresses in cultured human cells. Mol. Biol. Cell 15, 2361–2374 (2004).
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).
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).
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).
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).
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).
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).
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.
Teves, S. S. & Henikoff, S. Heat shock reduces stalled RNA polymerase II and nucleosome turnover genome-wide. Genes Dev. 25, 2387–2397 (2011).
Li, J. et al. Kinetic competition between elongation rate and binding of NELF controls promoter-proximal pausing. Mol. Cell 50, 711–722 (2013).
Lai, W. K. & Pugh, B. F. Genome-wide uniformity of human ‘open’ pre-initiation complexes. Genome Res. 27, 15–26 (2017).
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).
Xiao, H. et al. Dual functions of largest NURF subunit NURF301 in nucleosome sliding and transcription factor interactions. Mol. Cell 8, 531–543 (2001).
Tsukiyama, T. & Wu, C. Purification and properties of an ATP-dependent nucleosome remodeling factor. Cell 83, 1011–1020 (1995).
Badenhorst, P. et al. The Drosophila nucleosome remodeling factor NURF is required for Ecdysteroid signaling and metamorphosis. Genes. Dev. 19, 2540–2545 (2005).
Fujimoto, M. et al. RPA assists HSF1 access to nucleosomal DNA by recruiting histone chaperone FACT. Mol. Cell 48, 182–194 (2012).
Andersson, R. et al. Human gene promoters are intrinsically bidirectional. Mol. Cell 60, 346–347 (2015).
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).
Pugh, B. F. & Venters, B. J. Genomic organization of human transcription initiation complexes. PLoS ONE 11, 0149339 (2016).
He, Q., Johnston, J. & Zeitlinger, J. ChIP-nexus enables improved detection of in vivo transcription factor binding footprints. Nat. Biotechnol. 33, 395–401 (2015).
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.
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).
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).
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).
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).
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).
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).
Wu, C. et al. Purification and properties of Drosophila heat shock activator protein. Science 238, 1247–1253 (1987).
Åkerfelt, M. et al. Heat shock transcription factor 1 localizes to sex chromatin during meiotic repression. J. Biol. Chem. 285, 34469–34476 (2010).
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).
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).
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).
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).
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).
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).
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).
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).
Shao, W. & Zeitlinger, J. Paused RNA polymerase II inhibits new transcriptional initiation. Nat. Genet. 49, 1045–1051 (2017).
Gressel, S. et al. CDK9-dependent RNA polymerase II pausing controls transcription initiation. eLife 6, e29736 (2017).
Banerji, J., Rusconi, S. & Schaffner, W. Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell 27, 299–308 (1981).
Buecker, C. & Wysocka, J. Enhancers as information integration hubs in development: lessons from genomics. Trends Genet. 28, 276–284 (2012).
Long, H. K., Prescott, S. L. & Wysocka, J. Ever-changing landscapes: transcriptional enhancers in development and evolution. Cell 167, 1170–1187 (2016).
Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).
Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394 (2011).
Henriques, T. et al. Widespread transcriptional pausing and elongation control at enhancers. Genes Dev. 32, 26–41 (2018).
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).
Arner, E. et al. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science 347, 1010–1014 (2015).
Schaukowitch, K. et al. Enhancer RNA facilitates NELF release from immediate early genes. Mol. Cell 56, 29–42 (2014).
Bradner, J. E., Hnisz, D. & Young, R. A. Transcriptional addiction in cancer. Cell 168, 629–643 (2017).
Chen, F. X. et al. PAF1 regulation of promoter-proximal pause release via enhancer activation. Science 357, 1294–1298 (2017).
Dekker, J. & Misteli, T. Long-range chromatin interactions. Cold Spring Harb. Perspect. Biol. 7, a019356 (2015).
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).
Li, L. et al. Widespread rearrangement of 3D chromatin organization underlies polycomb-mediated stress-induced silencing. Mol. Cell 58, 216–231 (2015).
Galvani, A. & Thiriet, C. Nucleosome dancing at the tempo of histone tail acetylation. Genes 6, 607–621 (2015).
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).
Guo, Y. CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice. Proc. Natl. Acad. Sci. USA 109, 21081–21086 (2012).
Weintraub, A. S. et al. YY1 is a structural regulator of enhancer-promoter loops. Cell 171, 1573–1588 (2017).
Bai, P. Biology of poly(ADP-ribose) polymerases: the factotums of cell maintenance. Mol. Cell 58, 947–958 (2015).
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).
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).
Tulin, A. & Spradling, A. Chromatin loosening by poly(ADP)-ribose polymerase (PARP) at Drosophila puff loci. Science 299, 560–562 (2003).
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).
Martin, N. et al. PARP-1 transcriptional activity is regulated by sumoylation upon heat shock. EMBO J. 28, 3534–3548 (2009).
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).
Fujimoto, M. et al. The HSF1-PARP13-PARP1 complex facilitates DNA repair and promotes mammary tumorigenesis. Nat. Commun. 8, 1638 (2017).
Verger, A., Perdomo, J. & Crossley, M. Modification with SUMO. A role in transcriptional regulation. EMBO Rep. 4, 137–142 (2003).
Guo, C. & Henley, J. M. Wrestling with stress: roles of protein SUMOylation and deSUMOylation in cell stress response. IUBMB Life 66, 71–77 (2014).
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).
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).
Pellegrino, S. & Altmeyer, M. Interplay between ubiquitin, SUMO, and poly(ADP-ribose) in the cellular response to genotoxic stress. Front. Genet. 7, 63 (2016).
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).
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).
Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).
Tippens, N. D., Vihervaara, A. & Lis, J. T. Enhancer transcription: what, where, when, and why? Genes Dev. 32, 1–3 (2018).
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).
Shin, C., Feng, Y. & Manley, J. L. Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature 427, 553–558 (2004).
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.
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.
Proudfoot, N. J. Transcriptional termination in mammals: stopping the RNA polymerase II juggernaut. Science 352, aad9926 (2016).
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.
Grosso, A. R. et al. Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma. eLife 4, e09214 (2015).
Rutkowski, A. J. et al. Widespread disruption of host transcription termination in HSV-1 infection. Nat. Commun. 6, 7126 (2015).
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).
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).
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.
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).
Acosta-Alvear, D. et al. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol. Cell 27, 53–66 (2007).
Fiorese, C. J. et al. The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr. Biol. 26, 2037–2043 (2016).
Zhao, Q. et al. A mitochondrial specific stress response in mammalian cells. EMBO J. 21, 4411–4419 (2002).
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.
The authors declare no competing interests.
Publisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Unfolded protein response
(UPR). A cellular response that is triggered upon sensing of the accumulation of misfolded proteins.
Proteins that assist in folding, unfolding, assembly and disassembly of macromolecular structures.
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.
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.
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.
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.
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.
About this article
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
Struggle for survival: new insights into NELF condensation for adaptive transcriptional reprogramming
Molecular Cell (2021)
Nuclear Reorganization in Hippocampal Granule Cell Neurons from a Mouse Model of Down Syndrome: Changes in Chromatin Configuration, Nucleoli and Cajal Bodies
International Journal of Molecular Sciences (2021)
Genes & Genomics (2021)
Genes & Development (2021)
Stress-induced transcriptional memory accelerates promoter-proximal pause release and decelerates termination over mitotic divisions
Molecular Cell (2021)