Key Points
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Diverse studies ranging from RNA sequencing to characterization of chromatin modifications strongly indicate that there is a set of major types of core promoters that have similar function characteristics over metazoans. These three classes are: sharply defined TATA-dependent promoters, which are often tissue-specific; dispersed promoters with a broad expression and high CG content in mammals; and promoters that are active in development and are part of large CpG islands.
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Retrosposon elements can function as promoters, giving a new dimension to how promoters can evolve within a species.
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RNA polymerase II is even enriched at transcription start sites for inactive genes and can travel in the 3′-to-5′ direction (called backtracking).
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A wealth of non-coding RNAs that are associated with core promoters has been discovered. These are linked to different modes of biogenesis, but their function is not clear.
Abstract
Promoters are crucial for gene regulation. They vary greatly in terms of associated regulatory elements, sequence motifs, the choice of transcription start sites and other features. Several technologies that harness next-generation sequencing have enabled recent advances in identifying promoters and their features, helping researchers who are investigating functional categories of promoters and their modes of regulation. Additional features of promoters that are being characterized include types of histone modifications, nucleosome positioning, RNA polymerase pausing and novel small RNAs. In this Review, we discuss recent findings relating to metazoan promoters and how these findings are leading to a revised picture of what a gene promoter is and how it works.
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Acknowledgements
B.L. acknowledges the support of the Bergen Research Foundation, the Norwegian YFF project 180435, the Norwegian Research Foundation and the UK Medical Research Council. A.S. was supported by grants from the European Research Commission (FP7/2007-2013/ERC grant agreement 204135), The Novo Nordisk Foundation, The Lundbeck Foundation and the Danish Cancer Society. P.C. was supported by a grant from the Seventh Framework of the European Union Commission to the Dopaminet Consortium, the Modhep Consortium, the Braintrain Consortium, the Funding Program for the Next Generation World-Leading Researchers (NEXT Program) and a research grant to RIKEN Omics Science Center from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
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Piero Carninci is the author of a patent relating to the cap analysis of gene expression (CAGE) technology and is on the scientific advisory board of a company that licenses the CAGE technology. Neither Boris Lenhard nor Albin Sandelin declares any competing financial interests.
Glossary
- Transcription start sites
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(TSSs). Nucleotides in the genome that are the first to be transcribed into a particular RNA.
- Pre-initiation complex
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(PIC). A polypeptide complex consisting of RNA polymerase II and general transcription factors. This forms in the core promoter region around the transcription start site and primes RNA polymerase II for transcription.
- B recognition element
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(BRE). A core promoter element with consensus sequence SSRCGCC found upstream of TATA box.
- Cap analysis of gene expression
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(CAGE). A method for finding transcription start sites.
- Chromatin immunoprecipitation
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(ChIP). A method for finding DNA–protein interactions that is often combined with sequencing (ChIP–seq) or with microarray analysis (ChIP–chip).
- CpG island
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Genomic sequences that are not depleted of CG dinucleotides, which occurs by 5-methylcytosine deamination. They often overlap or are near to transcription start sites. Most definitions set a minimum length (for example, 200 or 500bp) and a minimum observed/expected CpG ratio.
- TATA box
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A T/A-rich sequence that lies upstream of TSSs.
- Initiator element
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(Inr element). A sequence pattern overlapping the TSSs.
- Downstream promoter element
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(DPE). This has the consensus sequence RGWCGTG and is common in Drosophila melanogaster genes 25–30 bp downstream of the transcription start site.
- Expressed sequence tag
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(EST). An older method that sequences parts of full-length RNAs.
- Polycomb group proteins
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(PcG proteins). These are epigenetic regulators of gene expression that silence target genes by establishing a repressive chromatin state. Because of their role in maintaining states of gene expression, PcG proteins have key roles in cell fate maintenance and transitions during development.
- Polycomb repressive complex 2
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(PRC2). A regulatory complex that catalyses trimethylation of histone H3 at lysine 27.
- Trithorax protein
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Proteins that belong to the Trithorax group (TrxG) form large complexes and maintain the stable and heritable expression of certain genes throughout development.
- Nucleosome occupancy
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A measure of the degree to which a certain DNA region is bound by a nucleosome.
- Nucleosome positioning
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The pattern of nucleosome occupancy along DNA.
- SWI/SNF
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A protein complex that can alter the positions of nucleosomes. It has ATP-dependent chromatin remodelling activity.
- CCCTC-binding factor
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(CTCF). A transcription factor, one role of which seems to be to define some chromatin boundaries that are associated with differential DNA accessibility.
- Transcription factories
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Nuclear compartments in which active transcription takes place; they have a high concentration of RNA polymerase II.
- Recapping
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A process by which an uncapped RNA 5′ end − for example, resulting from degradation − is stabilized by the addition of a cap structure.
- Cap structure
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A chemical structure found at the 5′ end of mature mRNAs that is used for mRNA stabilization and export to the cytosol.
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Lenhard, B., Sandelin, A. & Carninci, P. Metazoan promoters: emerging characteristics and insights into transcriptional regulation. Nat Rev Genet 13, 233–245 (2012). https://doi.org/10.1038/nrg3163
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DOI: https://doi.org/10.1038/nrg3163
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