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  • Review Article
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Born to run: control of transcription elongation by RNA polymerase II

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Abstract

The dynamic regulation of transcription elongation by RNA polymerase II (Pol II) is an integral part of the implementation of gene expression programmes during development. In most metazoans, the majority of transcribed genes exhibit transient pausing of Pol II at promoter-proximal regions, and the release of Pol II into gene bodies is controlled by many regulatory factors that respond to environmental and developmental cues. Misregulation of the elongation stage of transcription is implicated in cancer and other human diseases, suggesting that mechanistic understanding of transcription elongation control is therapeutically relevant. In this Review, we discuss the features, establishment and maintenance of Pol II pausing, the transition into productive elongation, the control of transcription elongation by enhancers and by factors of other cellular processes, such as topoisomerases and poly(ADP-ribose) polymerases (PARPs), and the potential of therapeutic targeting of the elongation stage of transcription by Pol II.

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Fig. 1: Establishment, maintenance and release of RNA polymerase II pausing.
Fig. 2: Release of RNA polymerase II pausing by P-TEFb-containing complexes.
Fig. 3: Post-translational modification of RNA polymerase II and histones at active genes with pausing and at active enhancers.
Fig. 4: Regulation of transcription elongation by enhancers.
Fig. 5: Cancer addiction into transcription elongation.

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F.X.C., E.R.S. and A.S. researched data for the article, made substantial contributions to the discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Ali Shilatifard.

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Glossary

Super elongation complex

(SEC). A complex containing the most active form of positive transcription elongation factor-b; required for almost all rapid inductions of transcription and for release of paused RNA polymerase II.

Pausing index

An estimate of RNA polymerase II (Pol II) promoter-proximal pausing; the ratio of Pol II occupancy at the promoter-proximal region compared with the gene body.

Travelling ratio

The ratio of gene-body RNA polymerase II (Pol II) to promoter-proximal Pol II.

Initiating Pol II

RNA polymerase II that is recruited by the general transcription factors and is involved in promoter melting before being released for transcription.

Paused Pol II

RNA polymerase II that has initiated non-productive transcription and is transiently pausing at the promoter-proximal region.

Bisulfite sequencing

Bisulfite deaminates unmethylated DNA cytosine into uracil, which can be used to infer the position of methylated cytosine through sequencing.

TATA box

A short AT-rich motif found in many RNA polymerase II promoters; bound by the general transcription factor TATA-binding protein.

G-quadruplex

(G4). A highly stable nucleic acid structure comprising two or more stacked guanine tetrads. Intramolecular G-quadruplexes formed in nascent RNA can contribute to RNA polymerase II pausing.

Mediator complex

A large multiprotein complex that interacts with transcription factors and RNA polymerase II. Mediator can promote enhancer–promoter looping to activate transcription and can also recruit transcription elongation factors.

Auxin-inducible degradation

In cells expressing a plant auxin-inducible E3 ubiquitin ligase, any protein of interest can be tagged for rapid degraded upon addition of auxin to the medium.

Acute protein degradation

Experimentally induced degradation of proteins by targeting them for proteasomal degradation.

Integrator complex

A large multiprotein complex found only in metazoans that can directly interact with RNA polymerase II; facilitates transcription and 3′-end processing of enhancer RNAs and small nuclear RNAs and recruitment of the super elongation complex to immediate early-response genes.

Nucleosome breathing

A property of nucleosomes whereby DNA at the edges of the histone core transiently unwrap and rewrap.

Pol II clamp

Part of the RNA polymerase II (Pol II) complex comprising the amino-terminal regions of RNA Pol II subunit 1 (Rpb1) and Rpb2, and the carboxy-terminal region of Rpb6, which swings over the Pol II active-site cleft to encase the DNA template and nascent RNA.

Cornelia de Lange syndrome

A developmental syndrome caused by heterozygous germline loss-of-function mutations in the cohesin loading protein nipped-B-like protein or in structural components of the cohesin ring.

CHOPS syndrome

A developmental syndrome with a similar phenotype to Cornelia de Lange syndrome that is caused by germline gain-of-function mutations in the super elongation complex scaffolding protein AF4/FMR2 family member 4.

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Chen, F.X., Smith, E.R. & Shilatifard, A. Born to run: control of transcription elongation by RNA polymerase II. Nat Rev Mol Cell Biol 19, 464–478 (2018). https://doi.org/10.1038/s41580-018-0010-5

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