Key Points
-
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.
-
Retrosposon elements can function as promoters, giving a new dimension to how promoters can evolve within a species.
-
RNA polymerase II is even enriched at transcription start sites for inactive genes and can travel in the 3′-to-5′ direction (called backtracking).
-
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Sandelin, A. et al. Mammalian RNA polymerase II core promoters: insights from genome-wide studies. Nature Rev. Genet. 8, 424–436 (2007).
Valen, E. & Sandelin, A. Genomic and chromatin signals underlying transcription start-site selection. Trends Genet. 27, 475–485 (2011).
Maston, G. A., Evans, S. K. & Green, M. R. Transcriptional regulatory elements in the human genome. Annu. Rev. Genomics Hum. Genet. 7, 29–59 (2006).
Riethoven, J.-J. M. Regulatory regions in DNA: promoters, enhancers, silencers, and insulators. Methods Mol. Biol. 674, 33–42 (2010).
Ohler, U. & Wassarman, D. A. Promoting developmental transcription. Development 137, 15–26 (2010).
Deaton, A. M. & Bird, A. CpG islands and the regulation of transcription. Genes Dev. 25, 1010–1022 (2011).
Kadonaga, J. T. Perspectives on the RNA polymerase II core promoter. WIREs Dev. Biol. 1, 40–51 (2012).
Carninci, P. et al. Genome-wide analysis of mammalian promoter architecture and evolution. Nature Genet. 38, 626–635 (2006). This is one of the most comprehensive early studies on TSS distributions in humans and mice.
Yamashita, R., Suzuki, Y., Sugano, S. & Nakai, K. Genome-wide analysis reveals strong correlation between CpG islands with nearby transcription start sites of genes and their tissue specificity. Gene 350, 129–136 (2005).
Yoshimura, K. et al. The cystic fibrosis gene has a “housekeeping”-type promoter and is expressed at low levels in cells of epithelial origin. J. Biol. Chem. 266, 9140–9144 (1991).
Ponjavic, J. et al. Transcriptional and structural impact of TATA-initiation site spacing in mammalian core promoters. Genome Biol. 7, R78 (2006).
Plessy, C. et al. Promoter architecture of mouse olfactory receptor genes. Genome Res. 22 Dec 2011 (doi:10.1101/gr.126201.111).
Rach, E. A. et al. Transcription initiation patterns indicate divergent strategies for gene regulation at the chromatin level. PLoS Genet. 7, e1001274 (2011). This is a study that correlated TSS shapes with chromatin mark information, showing the link between the two features.
FitzGerald, P. C., Sturgill, D., Shyakhtenko, A., Oliver, B. & Vinson, C. Comparative genomics of Drosophila and human core promoters. Genome Biol. 7, R53 (2006).
Ohler, U. Identification of core promoter modules in Drosophila and their application in accurate transcription start site prediction. Nucleic Acids Res. 34, 5943–5950 (2006).
Engstrom, P. G., Ho Sui, S. J., Drivenes, O., Becker, T. S. & Lenhard, B. Genomic regulatory blocks underlie extensive microsynteny conservation in insects. Genome Res. 17, 1898–1908 (2007).
Akalin, A. et al. Transcriptional features of genomic regulatory blocks. Genome Biol. 10, R38 (2009).
Rach, E. A., Yuan, H.-Y., Majoros, W. H., Tomancak, P. & Ohler, U. Motif composition, conservation and condition-specificity of single and alternative transcription start sites in the Drosophila genome. Genome Biol. 10, R73 (2009).
Hoskins, R. A. et al. Genome-wide analysis of promoter architecture in Drosophila melanogaster. Genome Res. 21, 182–185 (2011).
Hendrix, D. A., Hong, J.-W., Zeitlinger, J., Rokhsar, D. S. & Levine, M. S. Promoter elements associated with RNA Pol II stalling in the Drosophila embryo. Proc. Natl Acad. Sci. USA 105, 7762–7767 (2008).
van Heeringen, S. J. et al. Nucleotide composition-linked divergence of vertebrate core promoter architecture. Genome Res. 21, 410–421 (2011).
Grishkevich, V., Hashimshony, T. & Yanai, I. Core promoter T-blocks correlate with gene expression levels in C. elegans. Genome Res. 21, 707–717 (2011).
Parry, T. J. et al. The TCT motif, a key component of an RNA polymerase II transcription system for the translational machinery. Genes Dev. 24, 2013–2018 (2010).
Damgaard, C. K. & Lykke-Andersen, J. Translational coregulation of 5′TOP mRNAs by TIA-1 and TIAR. Genes Dev. 25, 2057–2068 (2011).
Perry, R. P. The architecture of mammalian ribosomal protein promoters. BMC Evol. Biol. 5, 15 (2005).
Ernst, J. & Kellis, M. Discovery and characterization of chromatin states for systematic annotation of the human genome. Nature Biotech. 28, 817–825 (2010).
Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nature Genet. 39, 1512–1516 (2007). This is one of several papers that used genomics methods to decipher stalling or poising; it also revealed functional tripartition of promoters based on RNAPII signal.
Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).
Schwartz, Y. B. et al. Alternative epigenetic chromatin states of Polycomb target genes. PLoS Genet. 6, e1000805 (2010).
Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011). This study uses an algorithm to segment the genome of nine ENCODE cell lines into regions with different functions based on the combination of epigenetic marks, revealing genome-wide epigenetic differences between promoter classes.
Kharchenko, P. V. et al. Comprehensive analysis of the chromatin landscape in Drosophila melanogaster. Nature 471, 480–485 (2011). This paper discusses a genome-wide chromatin landscape for D. melanogaster based on comprehensive histone modifications identifying combinatorial patterns, which is further integrated with chromosomes, genesand regulatory elements characteristics.
Izzo, A. & Schneider, R. Chatting histone modifications in mammals. Brief Funct. Genomics 9, 429–443 (2010).
Lee, J.-S., Smith, E. & Shilatifard, A. The language of histone crosstalk. Cell 142, 682–685 (2010).
Nozaki, T. et al. Tight associations between transcription promoter type and epigenetic variation in histone positioning and modification. BMC Genomics 12, 416 (2011).
Jiang, C. & Pugh, B. Nucleosome positioning and gene regulation: advances through genomics. Nature Rev. Genet. 10, 161–172 (2009).
Ioshikhes, I., Hosid, S. & Pugh, F. Variety of genomic DNA patterns for nucleosome positioning. Genome Res. 21, 1863–1871 (2011).
Radman-Livaja, M., Liu, C. L., Friedman, N., Schreiber, S. L. & Rando, O. J. Replication and active demethylation represent partially overlapping mechanisms for erasure of H3K4me3 in budding yeast. PLoS Genet. 6, e1000837 (2010).
Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009).
Subtil-Rodríguez, A. & Reyes, J. C. BRG1 helps RNA polymerase II to overcome a nucleosomal barrier during elongation, in vivo. EMBO Rep. 11, 751–757 (2010).
Hargreaves, D. C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145 (2009).
Fu, Y., Sinha, M., Peterson, C. L., Weng, Z. & van Steensel, B. The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome. PLoS Genet. 4, e1000138 (2008).
Kikuta, H. et al. Genomic regulatory blocks encompass multiple neighboring genes and maintain conserved synteny in vertebrates. Genome Res. 17, 545–555 (2007).
Visel, A., Rubin, E. M. & Pennacchio, L. A. Genomic views of distant-acting enhancers. Nature 461, 199–205 (2009).
Mikkelsen, T. S. et al. Comparative epigenomic analysis of murine and human adipogenesis. Cell 143, 156–169 (2010).
Roider, H. G., Lenhard, B., Kanhere, A., Haas, S. A. & Vingron, M. CpG-depleted promoters harbor tissue-specific transcription factor binding signals—implications for motif overrepresentation analyses. Nucleic Acids Res. 37, 6305–6315 (2009).
Soler, E. et al. A systems approach to analyze transcription factors in mammalian cells. Methods 53, 151–162 (2011).
Dean, A. In the loop: long range chromatin interactions and gene regulation. Brief Funct. Genomics 10, 3–10 (2011).
Cremer, T. & Cremer, M. Chromosome territories. Cold Spring Harb. Perspect. Biol. 2, a003889 (2010).
Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).
Lanctôt, C., Cheutin, T., Cremer, M., Cavalli, G. & Cremer, T. Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nature Rev. Genet. 8, 104–115 (2007).
Ferrai, C., de Castro, I. J., Lavitas, L., Chotalia, M. & Pombo, A. Gene positioning. Cold Spring Harb. Perspect. Biol. 2, a000588 (2010).
Muse, G. W. et al. RNA polymerase is poised for activation across the genome. Nature Genet. 39, 1507–1511 (2007).
Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007). This was one of several papers using genomics methods to decipher stalling or poising.
Nechaev, S. & Adelman, K. Pol. II waiting in the starting gates: regulating the transition from transcription initiation into productive elongation. Biochim. Biophys. Acta 1809, 34–45 (2011).
Gilmour, D. S. & Lis, J. T. RNA polymerase II interacts with the promoter region of the noninduced hsp70 gene in Drosophila melanogaster cells. Mol. Cell. Biol. 6, 3984–3989 (1986).
Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA Sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008).
Buratowski, S. Progression through the RNA polymerase II CTD Cycle. Mol. Cell 36, 541–546 (2009).
Ferrai, C. et al. Poised transcription factories prime silent uPA gene prior to activation. PLoS Biol. 8, e1000270 (2010).
Shaevitz, J. W., Abbondanzieri, E. A., Landick, R. & Block, S. M. Backtracking by single RNA polymerase molecules observed at near-base-pair resolution. Nature 426, 684–687 (2003).
Nechaev, S. et al. Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science 327, 335–338 (2010).
Gilchrist, D. A. et al. Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation. Cell 143, 540–551 (2010).
Faulkner, G. J. et al. The regulated retrotransposon transcriptome of mammalian cells. Nature Genet. 41, 563–571 (2009). This paper showed the large number of retrotransposon elements that are potential TSSs.
Frith, M. C. et al. A code for transcription initiation in mammalian genomes. Genome Res. 18, 1–12 (2008).
Faulkner, G. J. & Carninci, P. Altruistic functions for selfish DNA. Cell Cycle 8, 2895–2900 (2009).
Plessy, C. et al. Linking promoters to functional transcripts in small samples with nanoCAGE and CAGEscan. Nature Methods 7, 528–534 (2010).
Cohen, C. J., Lock, W. M. & Mager, D. L. Endogenous retroviral LTRs as promoters for human genes: a critical assessment. Gene 448, 105–114 (2009).
Schoenberg, D. R. & Maquat, L. E. Re-capping the message. Trends Biochem. Sci. 34, 435–442 (2009).
Jackowiak, P., Nowacka, M., Strozycki, P. M. & Figlerowicz, M. RNA degradome—its biogenesis and functions. Nucleic Acids Res. 39, 7361–7370 (2011).
Fejes-Toth, K. et al. Post-transcriptional processing generates a diversity of 5′-modified long and short RNAs. Nature 457, (2009) (1028).
Ni, T. et al. A paired-end sequencing strategy to map the complex landscape of transcription initiation. Nature Methods 7, 521–527 (2010).
Mercer, T. R. et al. Regulated post-transcriptional RNA cleavage diversifies the eukaryotic transcriptome. Genome Res. 20, 1639–1650 (2010).
O'Sullivan, J. M. et al. Gene loops juxtapose promoters and terminators in yeast. Nature Genet. 36, 1014–1018 (2004).
Kaderi, El, B., Medler, S., Raghunayakula, S. & Ansari, A. Gene looping is conferred by activator-dependent interaction of transcription initiation and termination machineries. J. Biol. Chem. 284, 25015–25025 (2009).
Perkins, K. J., Lusic, M., Mitar, I., Giacca, M. & Proudfoot, N. J. Transcription-dependent gene looping of the HIV-1 provirus is dictated by recognition of pre-mRNA processing signals. Mol. Cell 29, 56–68 (2008).
Tan-Wong, S. M., French, J. D., Proudfoot, N. J. & Brown, M. A. Dynamic interactions between the promoter and terminator regions of the mammalian BRCA1 gene. Proc. Natl Acad. Sci. USA 105, 5160–5165 (2008).
Kapranov, P. et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316, 1484–1488 (2007).
Preker, P. et al. PROMoter uPstream Transcripts share characteristics with mRNAs and are produced upstream of all three major types of mammalian promoters. Nucleic Acids Res. 39, 7179–7193 (2011).
Carninci, P. RNA dust: where are the genes? DNA Res. 17, 51–59 (2010).
Jacquier, A. The complex eukaryotic transcriptome: unexpected pervasive transcription and novel small RNAs. Nature Rev. Genet. 10, 833–844 (2009).
Taft, R. J., Kaplan, C. D., Simons, C. & Mattick, J. S. Evolution, biogenesis and function of promoter-associated RNAs. Cell Cycle 8, 2332–2338 (2009).
Valen, E. et al. Biogenic mechanisms and utilization of small RNAs derived from human protein-coding genes. Nature Struct. Mol. Biol. 18, 1075–1082 (2011).
Cernilogar, F. M. et al. Chromatin-associated RNA interference components contribute to transcriptional regulation in Drosophila. Nature 480, 391–395 (2011).
Basehoar, A. D., Zanton, S. J. & Pugh, B. F. Identification and distinct regulation of yeast TATA box-containing genes. Cell 116, 699–709 (2004).
Yamamoto, Y. Y. et al. Heterogeneity of Arabidopsis core promoters revealed by high-density TSS analysis. Plant J. 60, 350–362 (2009).
Woolfe, A. et al. Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol. 3, e7 (2005).
Seila, A. C. et al. Divergent transcription from active promoters. Science 322, 1849–1851 (2008).
Taft, R. J. et al. Tiny RNAs associated with transcription start sites in animals. Nature Genet. 41, 572–578 (2009).
Taft, R. J. et al. Nuclear-localized tiny RNAs are associated with transcription initiation and splice sites in metazoans. Nature Struct. Mol. Biol. 17, 1030–1034 (2010).
Izban, M. G. & Luse, D. S. The increment of SII-facilitated transcript cleavage varies dramatically between elongation competent and incompetent RNA polymerase II ternary complexes. J. Biol. Chem. 268, 12874–12885 (1993).
Mandal, S. S. et al. Functional interactions of RNA-capping enzyme with factors that positively and negatively regulate promoter escape by RNA polymerase II. Proc. Natl Acad. Sci. USA 101, 7572–7577 (2004).
Wasserman, W. W. & Sandelin, A. Applied bioinformatics for the identification of regulatory elements. Nature Rev. Genet. 5, 276–287 (2004).
Valen, E. et al. Genome-wide detection and analysis of hippocampus core promoters using DeepCAGE. Genome Res. 19, 255–265 (2009).
Kanamori-Katayama, M. et al. Unamplified cap analysis of gene expression on a single-molecule sequencer. Genome Res. 21, 1150–1159 (2011).
Affymetrix/Cold Spring Harbor Laboratory ENCODE Transcriptome Project. Post-transcriptional processing generates a diversity of 5′-modified long and short RNAs. Nature 457, 1028–1032 (2009). This study shows the large diversity of ncRNAs around promoters.
Hashimoto, S.-I. et al. 5′-end SAGE for the analysis of transcriptional start sites. Nature Biotech. 22, 1146–1149 (2004).
Ng, P. et al. Gene identification signature (GIS) analysis for transcriptome characterization and genome annotation. Nature Methods 2, 105–111 (2005).
Thomas, M. F. & Ansel, K. M. Construction of small RNA cDNA libraries for deep sequencing. Methods Mol. Biol. 667, 93–111 (2010).
Kawaji, H. et al. Hidden layers of human small RNAs. BMC Genomics 9, 157 (2008).
Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).
The ENCODE Project Consortium. A user's guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 9, e1001046 (2011).
Gilchrist, D. A. et al. NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly. Genes Dev. 22, 1921–1933 (2008).
Gries, T. J., Kontur, W. S., Capp, M. W., Saecker, R. M. & Record, M. T. One-step DNA melting in the RNA polymerase cleft opens the initiation bubble to form an unstable open complex. Proc. Natl Acad. Sci. USA 107, 10418–10423 (2010).
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
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
-
(TSSs). Nucleotides in the genome that are the first to be transcribed into a particular RNA.
- Pre-initiation complex
-
(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
-
(BRE). A core promoter element with consensus sequence SSRCGCC found upstream of TATA box.
- Cap analysis of gene expression
-
(CAGE). A method for finding transcription start sites.
- Chromatin immunoprecipitation
-
(ChIP). A method for finding DNA–protein interactions that is often combined with sequencing (ChIP–seq) or with microarray analysis (ChIP–chip).
- CpG island
-
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
-
A T/A-rich sequence that lies upstream of TSSs.
- Initiator element
-
(Inr element). A sequence pattern overlapping the TSSs.
- Downstream promoter element
-
(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
-
(EST). An older method that sequences parts of full-length RNAs.
- Polycomb group proteins
-
(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
-
(PRC2). A regulatory complex that catalyses trimethylation of histone H3 at lysine 27.
- Trithorax protein
-
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
-
A measure of the degree to which a certain DNA region is bound by a nucleosome.
- Nucleosome positioning
-
The pattern of nucleosome occupancy along DNA.
- SWI/SNF
-
A protein complex that can alter the positions of nucleosomes. It has ATP-dependent chromatin remodelling activity.
- CCCTC-binding factor
-
(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
-
Nuclear compartments in which active transcription takes place; they have a high concentration of RNA polymerase II.
- Recapping
-
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
-
A chemical structure found at the 5′ end of mature mRNAs that is used for mRNA stabilization and export to the cytosol.
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrg3163