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  • Review Article
  • Published:

Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans

Nature Reviews Genetics volume 13, pages 720–731 (2012)Cite this article

Subjects

Key Points

  • Pausing is now recognized to be a pervasive feature of promoters in mammals and Drosophila melanogaster, and the evidence supporting this from genome-wide studies is presented.

  • The nomenclature of different promoter-associated RNA polymerase II (Pol II) species is explicitly defined in an effort to provide consistency in future literature.

  • The known mechanistic features of Pol II pausing and its release to productive elongation are described. Most genes are associated with factors that establish and release paused Pol II and therefore appear to progress through this step, although only a subset of genes appears to be directly regulated by pausing.

  • Multiple lines of evidence support the idea that Pol II and nucleosomes compete for promoter binding and suggest that a crucial role of paused Pol II involves maintenance of accessible promoter chromatin architecture.

  • Although pausing has been connected to extremely rapid and synchronous activation of genes, pausing is also highly associated with constitutively expressed genes that encode signalling and transcription factors. Pausing provides a mechanism to tune these key genes to cellular and external regulatory cues.

  • Pausing provides a point of regulation that is distinct from Pol II recruitment and initiation, and this may facilitate the integration of multiple cellular signals. Distinct signals that act through diverse targeted transcription factors can regulate different steps in the transcription pathway and provide a highly modulated transcriptional response at individual genes.

  • Pol II pausing and release occur at a point when 5′ end RNA processing and phosphorylation of the Pol II carboxy-terminal domain occurs. We speculate that by coupling RNA processing to the status and activity of Pol II itself, the cell ensures that nascent RNA is properly protected from degradation and efficiently matures into a functional mRNA.

Abstract

Recent years have witnessed a sea change in our understanding of transcription regulation: whereas traditional models focused solely on the events that brought RNA polymerase II (Pol II) to a gene promoter to initiate RNA synthesis, emerging evidence points to the pausing of Pol II during early elongation as a widespread regulatory mechanism in higher eukaryotes. Current data indicate that pausing is particularly enriched at genes in signal-responsive pathways. Here the evidence for pausing of Pol II from recent high-throughput studies will be discussed, as well as the potential interconnected functions of promoter-proximally paused Pol II.

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Figure 1: Defining the terms used to describe promoter-associated Pol II complexes.
Figure 2: Patterns of Pol II distribution across gene regions.
Figure 3: Establishment and release of paused Pol II.
Figure 4: Illustrations of the main hypotheses for the functions of Pol II pausing.

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Acknowledgements

We thank the members of the Lis and Adelman laboratories for their helpful discussions on this Review. Funding for this work was provided by US National Institutes of Health (NIH) grant GM25232 to J.L. and the Intramural Research Program of the NIH National Institute of Environmental Health Sciences (Z01 ES101987) to K.A.

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  1. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, 27709, North Carolina, USA

    Karen Adelman

  2. Cornell University, Molecular Biology and Genetics, Biotechnology Building, Ithaca, 14853, New York, USA

    John T. Lis

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Nature Reviews Genetics Series on Modes of transcriptional regulation

Glossary

Pre-initiation complex

(PIC). An entry form of Pol II in a complex with general transcription factors in which the polymerase is bound to the promoter DNA but has not yet initiated RNA synthesis.

Heat shock genes

(Hsp genes). These genes are a set of highly conserved genes that encode molecular chaperones. These genes are rapidly induced in cells or organisms in response to various cellular stresses, including a several-degree increase in temperature.

Long terminal repeat

(LTR). In HIV, this promoter resides in a region of LTRs. Transcription from this promoter produces both viral proteins and new RNA genomes.

Ligation-meditated PCR

(LM-PCR). A technique that can be used to map the ends of DNA fragments precisely from a specific region of the genome. Small DNA linkers are added to ends of DNA samples and then primers that are complementary to this linker are combined with a sequence-specific primer to amplify the DNA of interest by PCR.

CpG islands

Regions of higher-than-normal CpG sequence content that are on average 1,000 base pairs in length. Such regions contain ~70% of all mammalian promoters, including both genes that are highly regulated and broadly expressed.

Polycomb

Regulate chromatin structure to contribute to epigenetic inheritance of a repressed state. They form several complexes, which are broadly defined as Polycomb repressive complexes 1 and 2 (PRC1 and PRC2), and these are thought to compact chromatin structure.

Bivalent genes

Exhibit histone modifications that are characteristic of both gene repression and activation. These genes display low levels of Pol II occupancy and activity and are hypothesized to be poised for activation during development.

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Adelman, K., Lis, J. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat Rev Genet 13, 720–731 (2012). https://doi.org/10.1038/nrg3293

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