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Modes of transcriptional regulation

Molecular mechanisms driving transcriptional stress responses

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.

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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.

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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.

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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.

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Correspondence to John T. Lis.

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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.

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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

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