RNA polymerase II (Pol II) elongation is a highly regulated process.
Regulation of transcription is often mediated at the level of promoter-proximal pausing of Pol II, in which Pol II is paused approximately 30–60 nucleotides downstream of the transcription start site (TSS) and awaits recruitment of kinase positive transcription elongation factor-b (P-TEFb).
P-TEFb is the main factor required to release paused Pol II from the promoter-proximal region, and can directly or indirectly be recruited by many factors, including bromodomain-containing protein 4 (BRD4) and the super elongation complex (SEC).
Elongation rates throughout the gene body are not uniform but vary between, and within genes, and can range from ∼1 to 6 kb per minute.
Transient slowdown of Pol II is observed up to 15 kb downstream of the TSS, at exons and near the poly(A) cleavage site.
Elongation rates can affect co-transcriptional RNA processes such as splicing and termination, as well as genome stability.
Recent advances in sequencing techniques that measure nascent transcripts and that reveal the positioning of RNA polymerase II (Pol II) have shown that the pausing of Pol II in promoter-proximal regions and its release to initiate a phase of productive elongation are key steps in transcription regulation. Moreover, after the release of Pol II from the promoter-proximal region, elongation rates are highly dynamic throughout the transcription of a gene, and vary on a gene-by-gene basis. Interestingly, Pol II elongation rates affect co-transcriptional processes such as splicing, termination and genome stability. Increasing numbers of factors and regulatory mechanisms have been associated with the steps of transcription elongation by Pol II, revealing that elongation is a highly complex process. Elongation is thus now recognized as a key phase in the regulation of transcription by Pol II.
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The authors thank C. Danko, F. Duarte and D. Mahat for their critical evaluation of the manuscript. J.T.L. was supported by NIGMS (National Institute of General Medical Sciences) from the US National Institutes of Health under award GM25232. I.J. was supported by a European Research Council Advanced Grant (ERCadv-671274). The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health or the European Research Council.
The authors declare no competing financial interests.
A small drug that inhibits P-TEFb kinase activity. It is used to characterize pausing and elongation complexes, and to measure elongation rates genome-wide.
- Carboxy-terminal domain (CTD) of Pol II
The CTD of Pol II, which is positioned at the end of the largest Pol II subunit, is an unstructured, yet evolutionarily conserved, domain that comprises many tandem copies of the consensus heptapeptide YSPTSPS. Phosphorylation of these repeats is crucial for the regulation of Pol II function.
- +1 nucleosome
The first well-positioned nucleosome downstream of the transcription start site, which can form a barrier for elongating Pol II and might increase Pol II promoter-proximal pausing. The position of the +1 nucleosome depends on transcription, nucleosome remodelling, and DNA sequences.
- Pre-initiation complex
(PIC). A complex consisting of general transcription factors and Pol II that binds at the transcription start site, before DNA melting and transcription initiation.
- Open promoters
Promoters that are nucleosome-free and easily accessible to transcription factors and Pol II. These promoters are primed for, or undergo, active transcription.
- DNA melting
The process of unwinding and 'opening' double-stranded DNA at the transcription start site by general transcription factors to form a transcription bubble, which allows initiation of Pol II activity.
- General transcription factors
(GTFs). Factors that bind the core promoter region, facilitate DNA melting and transcription bubble formation, and position Pol II to initiate transcription and escape the promoter region.
Regulatory regions that bind sequence-specific TFs and have potential transcription start sites and can interact with gene promoters three dimensionally to regulate gene expression.
A multisubunit co-activator complex that can interact with TFs, GTFs and Pol II and is essential for transcription. Mediator has been shown to mediate interaction between enhancers and gene promoters, for example at super-enhancers.
- Enhancer RNAs
(eRNAs). RNAs that derive from the transcription of enhancers. Some of these enhancer-derived RNAs contribute to enhancer function.
- Histone chaperones
Proteins that facilitate the movement of Pol II through chromatin by loosening the nucleosome–DNA interactions and then restoring these in the wake of Pol II.
An RNA–DNA hybrid structure formed during the transcription of a sequence with high GC-content that has the potential to pause Pol II. R-loops are associated with transcription termination and genome instability.
- Exon skipping
A form of alternative splicing, in which an exon is 'skipped' and removed as part of the flanking introns during transcription.
- MLL–ELL fusions
A fusion formed between the MLL gene (which encodes mixed-lineage leukaemia) and the ELL gene (which encodes eleven-nineteen Lys-rich leukaemia) that greatly increases the leukaemogenic potential of a cell.
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Jonkers, I., Lis, J. Getting up to speed with transcription elongation by RNA polymerase II. Nat Rev Mol Cell Biol 16, 167–177 (2015). https://doi.org/10.1038/nrm3953
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Nature Communications (2022)