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Eukaryotic core promoters and the functional basis of transcription initiation

Abstract

RNA polymerase II (Pol II) core promoters are specialized DNA sequences at transcription start sites of protein-coding and non-coding genes that support the assembly of the transcription machinery and transcription initiation. They enable the highly regulated transcription of genes by selectively integrating regulatory cues from distal enhancers and their associated regulatory proteins. In this Review, we discuss the defining properties of gene core promoters, including their sequence features, chromatin architecture and transcription initiation patterns. We provide an overview of molecular mechanisms underlying the function and regulation of core promoters and their emerging functional diversity, which defines distinct transcription programmes. On the basis of the established properties of gene core promoters, we discuss transcription start sites within enhancers and integrate recent results obtained from dedicated functional assays to propose a functional model of transcription initiation. This model can explain the nature and function of transcription initiation at gene starts and at enhancers and can explain the different roles of core promoters, of Pol II and its associated factors and of the activating cues provided by enhancers and the transcription factors and cofactors they recruit.

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Fig. 1: Properties and function of core promoters and enhancers.
Fig. 2: Regulation of different steps of transcription from core promoters.
Fig. 3: Sequence-encoded specificity of core promoters towards enhancers and activation by specific transcription factors and cofactors.
Fig. 4: Functional model of transcription initiation at genomic promoters and enhancers.

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Acknowledgements

The authors thank F. Mürdter, M. A. Zabidi, P. R. Andersen, C. Plaschka and C. Bernecky for helpful comments on the manuscript. V.H. is supported by a long-term postdoctoral fellowship from the Human Frontier Science Program (HFSP, grant number LT000324/2016-L). Research in the Stark group is supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 647320) and by the Austrian Science Fund (FWF, F4303-B09). Basic research at the Institute of Molecular Pathology (IMP), Vienna, Austria, is supported by Boehringer Ingelheim GmbH and the Austrian Research Promotion Agency (FFG).

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Nature Reviews Molecular Cell Biology thanks S. Spicuglia and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Glossary

Core promoter

A short sequence flanking the transcription start site that is sufficient to assemble the RNA polymerase II transcription machinery and initiate transcription.

General transcription factors

(GTFs). Proteins that together with RNA polymerase II constitute the transcription machinery at the core promoter.

Enhancers

DNA sequences that contain binding sites for sequence-specific transcription factors and increase the level of transcription from distal core promoters, independently of distance and orientation.

Transcription factors

Proteins that directly bind a specific DNA sequence through their DNA-binding domain and regulate the level of transcription by recruiting RNA polymerase II or transcriptional cofactors through their trans-activation domain.

Transcriptional cofactors

Proteins that do not directly bind DNA but are recruited by DNA-binding transcription factors to regulate transcription of target genes.

Enhancer RNAs

(eRNAs). Short ( <2 kb) unstable non-coding RNAs, usually not spliced or polyadenylated, which are transcribed from enhancers and are rapidly degraded by the exosome.

Nucleosome-depleted region

(NDR). A genomic region depleted of canonical nucleosomes; it is usually associated with active regulatory elements such as promoters and enhancers.

Promoters

Genomic regions encompassing a gene core promoter and an upstream proximal promoter, which together autonomously drive transcription.

Proximal promoter

A transcription-activating sequence immediately upstream of the core promoter (typically up to 250 bp upstream of the transcription start site) that contains binding sites for sequence-specific transcription factors and functions like an enhancer.

Pre-initiation complex

(PIC). A large complex of proteins, including RNA polymerase II and its general transcription factors, that assembles at core promoters and is required for transcription initiation.

CpG islands

(CGIs). GC-rich genomic sequences with a frequency of CpG dinucleotides that is higher than that found in the rest of the genome (which is generally depleted of CpG dinucleotides in mammals).

Piwi-interacting RNA

A type of small non-coding RNA (26–31 nucleotides) that interacts with Argonaute proteins from the Piwi family and mediates transcriptional and post-transcriptional gene silencing of transposable elements.

SAGA complex

SPT–ADA–GCN5-acetyltransferase (SAGA) is a co-activator complex with different chromatin-modifying modules, including, for example, histone acetyltransferase GCN5.

Promoter-proximal pausing

Pausing of RNA polymerase II downstream of the transcription start site; this process controls the transition into productive transcription elongation.

Enhancer responsiveness

The extent to which transcription from a core promoter is induced by a distal enhancer.

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Haberle, V., Stark, A. Eukaryotic core promoters and the functional basis of transcription initiation. Nat Rev Mol Cell Biol 19, 621–637 (2018). https://doi.org/10.1038/s41580-018-0028-8

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