Mammalian Heat Shock Response and Mechanisms Underlying Its Genome-wide Transcriptional Regulation

Mahat, Dig Bijay; Salamanca, H. Hans; Duarte, Fabiana M.; Danko, Charles G.; Lis, John T.

doi:10.1016/j.molcel.2016.02.025

Cited by 350 publications

(553 citation statements)

References 55 publications

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“…Furthermore, our results indicate that HS activation of HSF-dependent genes is regulated at the level of pausing release, whereas HS repression of thousands of genes is regulated at the step of transcription initiation in Drosophila, and this process is independent of HSF. Very recently, we showed in mice that HS activation is similarly regulated by HSF at the level of pause release; however, in contrast to Drosophila, HS repression of genes is also mediated at pause release (Mahat et al 2016). In both mammals and Drosophila, the widespread transcriptional repression is independent of HSF.…”

Section: Discussionmentioning

confidence: 98%

Transcription factors GAF and HSF act at distinct regulatory steps to modulate stress-induced gene activation

et al. 2016

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The coordinated regulation of gene expression at the transcriptional level is fundamental to development and homeostasis. Inducible systems are invaluable when studying transcription because the regulatory process can be triggered instantaneously, allowing the tracking of ordered mechanistic events. Here, we use precision run-on sequencing (PRO-seq) to examine the genome-wide heat shock (HS) response in Drosophila and the function of two key transcription factors on the immediate transcription activation or repression of all genes regulated by HS. We identify the primary HS response genes and the rate-limiting steps in the transcription cycle that GAGA-associated factor (GAF) and HS factor (HSF) regulate. We demonstrate that GAF acts upstream of promoterproximally paused RNA polymerase II (Pol II) formation (likely at the step of chromatin opening) and that GAF-facilitated Pol II pausing is critical for HS activation. In contrast, HSF is dispensable for establishing or maintaining Pol II pausing but is critical for the release of paused Pol II into the gene body at a subset of highly activated genes. Additionally, HSF has no detectable role in the rapid HS repression of thousands of genes.

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Section: Discussionmentioning

confidence: 98%

Transcription factors GAF and HSF act at distinct regulatory steps to modulate stress-induced gene activation

et al. 2016

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“…Consequently, measures of the exact location of transcribing Pol II complexes across the genome have revealed the breath of gene and enhancer regulation upon heat and celastrol stresses, as well as the mechanistic steps at which the transcriptional reprogramming is executed 9–11,27–28 . Moreover, high-resolution chromatin analyses have uncovered stress-induced changes in nucleosome dynamics 29 , trans -activator binding 10,21,30–32 , and chromatin states 11,27,29 , both at transcribed and untranscribed loci.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms driving transcriptional stress responses

Vihervaara¹,

Duarte²,

Lis³

2018

Nat Rev Genet

212

224

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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 on 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.

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“…Stress is also known to affect pause release, which is the transition of RNA polymerase II (Pol-II) from a pause site located within 100 bp of the promoter into efficient transcription elongation. A hallmark example of promoter proximal pausing is that of the Hsp70 gene in Drosophila, where pause release is triggered by heat shock, leading to a rapid boost in Hsp70 transcription (3,4); this phenomenon has been recently shown to be a major part of the mammalian transcriptional response to heat shock (5). Other transcription-related processes such as chromatin modification (6) and splicing (7) are also regulated by stress (reviewed in refs.…”

mentioning

confidence: 99%

Comparative analysis reveals genomic features of stress-induced transcriptional readthrough

Vilborg

Sabath

Wiesel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

120

148

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Transcription is a highly regulated process, and stress-induced changes in gene transcription have been shown to play a major role in stress responses and adaptation. Genome-wide studies reveal prevalent transcription beyond known protein-coding gene loci, generating a variety of RNA classes, most of unknown function. One such class, termed downstream of gene-containing transcripts (DoGs), was reported to result from transcriptional readthrough upon osmotic stress in human cells. However, how widespread the readthrough phenomenon is, and what its causes and consequences are, remain elusive. Here we present a genome-wide mapping of transcriptional readthrough, using nuclear RNA-Seq, comparing heat shock, osmotic stress, and oxidative stress in NIH 3T3 mouse fibroblast cells. We observe massive induction of transcriptional readthrough, both in levels and length, under all stress conditions, with significant, yet not complete, overlap of readthrough-induced loci between different conditions. Importantly, our analyses suggest that stress-induced transcriptional readthrough is not a random failure process, but is rather differentially induced across different conditions. We explore potential regulators and find a role for HSF1 in the induction of a subset of heat shock-induced readthrough transcripts. Analysis of public datasets detected increases in polymerase II occupancy in DoG regions after heat shock, supporting our findings. Interestingly, DoGs tend to be produced in the vicinity of neighboring genes, leading to a marked increase in their antisense-generating potential. Finally, we examine genomic features of readthrough transcription and observe a unique chromatin signature typical of DoG-producing regions, suggesting that readthrough transcription is associated with the maintenance of an open chromatin state.transcriptional readthrough | stress response | transcription regulation

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Mammalian Heat Shock Response and Mechanisms Underlying Its Genome-wide Transcriptional Regulation

Cited by 350 publications

References 55 publications

Transcription factors GAF and HSF act at distinct regulatory steps to modulate stress-induced gene activation

Transcription factors GAF and HSF act at distinct regulatory steps to modulate stress-induced gene activation

Molecular mechanisms driving transcriptional stress responses

Comparative analysis reveals genomic features of stress-induced transcriptional readthrough

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