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Transcriptional Regulatory Elements in the Human Genome
Abstract
The faithful execution of biological processes requires a precise and carefully orchestrated set of steps that depend on the proper spatial and temporal expression of genes. Here we review the various classes of transcriptional regulatory elements (core promoters, proximal promoters, distal enhancers, silencers, insulators/boundary elements, and locus control regions) and the molecular machinery (general transcription factors, activators, and coactivators) that interacts with the regulatory elements to mediate precisely controlled patterns of gene expression. The biological importance of transcriptional regulation is highlighted by examples of how alterations in these transcriptional components can lead to disease. Finally, we discuss the methods currently used to identify transcriptional regulatory elements, and the ability of these methods to be scaled up for the purpose of annotating the entire human genome.
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“since transcriptional regulatory elements are likely to be contained within these intervals and that there is thus merit in capturing the variation within these regions42.”
From Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways (2015) · cites this paper as [42]
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Haberle, V., & Lenhard, B. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.01.014 · Cited by 94
“Various core promoter elements have been identified in eukaryotic promoters and include a TATA-box, an Initiator (Inr), a Downstream Promoter Element (DPE), a Downstream Core Element (DCE), a TFIIB-Recognition Element (BRE), and a Motif Ten Element (MTE) [4] (Fig.”
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Vermunt, M. W., Reinink, P., Korving, J., de Bruijn, E., Creyghton, P. M., Başak, O., Geeven, G., Toonen, P. W., Lansu, N. R., Meunier, C., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.023 · Cited by 86
“While the core promoter of a gene constitutes the site where the transcriptional initiation complex is formed, enhancer elements are defined as regions in the genome that regulate core-promoter activity independent of distance or orientation (Maston et al., 2006).”
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“Although such promoters may incorporate some exonic sequence, it was shown that downstream elements also regulate transcription [76], and therefore including the first kilobase of gene bodies – provided that protein-coding gene properties such as codon bias are controlled for – can provide valuable regulatory Figure 3.”
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“Variants on the active sites of these interactions, or regulatory elements (8), have been shown to be driving forces of evolution (9, 10) and disease (11).”
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“The resultant BAC construct included the promoter and a large flanking region (which extended 85 kb upstream and 50 kb downstream) that contained known cis-acting regulatory elements to recapitulate the expression pattern of the endogenous loci (Maston et al., 2006).”
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“Transcription factors (TF) are among the most fundamental elements regulating gene expression and, with different co-factors, that regulate the transcription.(60) Post-transcriptional modification is attained by a similar combinatorial complexity of RBPs and protein-protein interactions.”
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“Whilst promoter elements lie proximal to the transcriptional start site (TSS) and are responsible for basal gene transcription, enhancers can be kilobases or megabases from the gene they regulate and are associated with cell- and tissue-specific expression (6,7).”
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“Cis-regulatory elements are genomic regions that transcription factors bind in order to modify the expression of a target gene [4].”
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“In case of hypomethylated DMRs, ~46% (1792) and ~53% (2074) DMRs mapped to gene body and intergenic regions respectively while approximately 1% of DMRs were associated with promoter (34) and TES (27) (Fig.”
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Leveraging massively parallel reporter assays for evolutionary questions
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“These elements are typically short sequences, on the order of 100s to 1000s of base pairs, that can be located within, close to, or distal to the genes they regulate (although in mammals they are often within 1 megabase [7, 10]).”
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“Promoters are a group of better-characterized proximal regions (3).”
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“These cis-regulatory elements (CREs) are often located in the non-coding genomic regions, which make up of over 98% of the human genome [2].”
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“These works have defined several types of cis-acting transcriptional regulators, including promoters, enhancers, insulators and locus control regions (LCR) (1,4,5) and the trans-acting factors that bind to them.”
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Distal enhancers: new insights into heart development and disease
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Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype
Jabbari, E., Woodside, J., Tan, M. M. X., Shoai, M., Pittman, A. M., Ferrari, R., Mok, K. Y., Zhang, D., Reynolds, R. H., de Silva, R., et al. (2018) · Annals of Neurology · doi:10.1002/ana.25308 · Cited by 53
The impact of inducible promoters in transgenic plant production and crop improvement
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“Generally, transcription factors recognize highly conserved sequences (6 to 12 bp long) upstream target genes [35].”
BackgroundDNA sequence and structural properties as predictors of human and mouse promoters
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Landscapes and archipelagos: spatial organization of gene regulation in vertebrates
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Genome-wide analysis of core promoter structures inSchizosaccharomyces pombewith DeepCAGE
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The Chromatin Remodeler CHD8 Is Required for Activation of Progesterone Receptor-Dependent Enhancers
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“Enhancers were originally defined as regulatory sequences that can activate gene expression independently of their proximity or orientation with respect to their target genes [5].”
BackgroundNutritional regulation of genome-wide association obesity genes in a tissue-dependent manner
Yoganathan, P., Karunakaran, S., Ho, M. M., & Clee, S. M. (2012) · Nutrition & Metabolism · doi:10.1186/1743-7075-9-65 · Cited by 44
“Transcriptional regulatory elements can be located before, within, or even following a gene, and can be located at substantial distance (up to 1 Mb) from the gene [38].”
BackgroundCremer, M., Schmid, V. J., Kraus, F., Markaki, Y., Hellmann, I., Maiser, A., Leonhardt, H., John, S., Stamatoyannopoulos, J. A., & Cremer, T. (2017) · Epigenetics & Chromatin · doi:10.1186/s13072-017-0146-0 · Cited by 45
“Background Transcription regulatory elements (TREs) such as promoters, enhancers or insulators comprise non-coding sequences located within or in close vicinity to a gene but are also found up to ~1 Mb distally from their genes [1, 2].”
BackgroundJacobsen, B. M., Jambal, P., Schittone, S. A., & Horwitz, K. B. (2009) · Molecular Endocrinology · doi:10.1210/me.2009-0048 · Cited by 44
“Note that CpG-rich promoters often contain a TFIIB-recognition element to launch transcription, thereby bypassing the need for a TATA box (30).”
BackgroundUltra-Rare Mutation in Long-Range Enhancer Predisposes to Thyroid Carcinoma with High Penetrance
He, H., Li, W., Wu, D., Nagy, R. S., Liyanarachchi, S., Akagi, K., Jendrzejewski, J., Jiao, H., Hoag, K. W., Wen, B., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061920 · Cited by 44
“Transcriptional regulatory elements may represent major sites where mutations contribute to human disease [39,40].”
Inayat, N., Khan, M., Iqbal, N., Khan, S. A., Raza, M., Khan, D. M., Khan, A., & Wei, D. (2021) · IEEE Access · doi:10.1109/access.2021.3062291 · Cited by 43
“The enhancers can be found up to 1 Mbp (1,000,000 bp) at distance from a gene and exist in various chromosomes which makes the identification of the enhancers a challenging job [2], [3].”
BackgroundAntoniani, C., Romano, O., & Miccio, A. (2017) · Stem Cells Translational Medicine · doi:10.1002/sctm.17-0192 · Cited by 50
Mossine, V. V., Waters, J. K., Hannink, M., & Mawhinney, T. P. (2013) · PLoS ONE · doi:10.1371/journal.pone.0085494 · Cited by 42
“Random exogenous polynucleotide integration into the host DNA often leads to the transgene silencing [17].”
BackgroundNon-canonical TAF complexes regulate active promoters in human embryonic stem cells
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“Previous studies have reported tissue-specific TAF variants and alterations in TAF expression (reviewed in D’Alessio et al., 2009; Müller et al., 2010), but the composition of hESC TAFs is unprecedented and is likely Figure 4.”
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Kuscu, C., Mammadov, R., Czikora, Á., Unlu, H., Tufan, T., Fischer, N. L., Arslan, Ş., Bekiranov, S., Kanemaki, M. T., & Adli, M. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.08.001 · Cited by 42
Ab initio thermodynamic modeling of distal multisite transcription regulation
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Predictive modelling of gene expression from transcriptional regulatory elements
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“Significant regulation of eukaryotic gene expression is known to occur at the level of transcriptional initiation and control [3].”
BackgroundFang, J., Lin, A., Qiu, W., Cai, H., Umar, M., Chen, R., & Ming, R. (2016) · Frontiers in Plant Science · doi:10.3389/fpls.2016.00855 · Cited by 41
“Or the insertions might muck up the various classes of transcriptional regulatory elements adjacent to the genes that they regulate, such as core/proximal promoters, distal enhancers, silencers, insulators/boundary elements, and locus control regions (LCR) (Maston et al., 2006), hence affecting the controlled patterns…”
BackgroundInfluentialTranscription Factors in Cartilage Homeostasis and Osteoarthritis
Neefjes, M., van Caam, A., & van der Kraan, P. M. (2020) · Biology · doi:10.3390/biology9090290 · Cited by 44
“For this, TFs recognize highly conserved unique sequences of nucleotides of approximately 6 to 12 base pairs long [25].”
BackgroundEvolution of DNA-Binding Sites of a Floral Master Regulatory Transcription Factor
Muiño, J. M., de Bruijn, S., Pajoro, A., Geuten, K. P., Vingron, M., Angenent, G. C., & Kaufmann, K. (2015) · Molecular Biology and Evolution · doi:10.1093/molbev/msv210 · Cited by 41
“The classical definition of enhancers identifies these elements as insensitive to changes in position and orientation relative to the start of the gene (Maston et al. 2006).”
BackgroundA super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer
Antal, C. E., Oh, T. G., Aigner, S., Luo, E., Yee, B. A., Campos, T., Tiriac, H., Rothamel, K. L., Zhang, C., Jiao, H., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40798-6 · Cited by 40
Lemp, N. A., Hiraoka, K., Kasahara, N., & Logg, C. R. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks451 · Cited by 40
“Although newer approaches for identifying regulatory elements, such as those based on chromatin immunoprecipitation, have yielded an abundance of information on protein–DNA interactions, plasmid reporter assays remain the favored method for assessing the functional activity in candidate regulatory sequences (2,3).”
MethodSheffield, N. C., & Furey, T. S. (2012) · Genes · doi:10.3390/genes3040651 · Cited by 37
“Open chromatin, and even evidence for a bound transcription factor, implies but does not demonstrate regulatory potential [24].”
BackgroundHemberg, M., Gray, J. M., Cloonan, N., Kuersten, S., Grimmond, S. M., Greenberg, M. E., & Kreiman, G. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks477 · Cited by 39
“Such sites include enhancers, insulators and silencers (1,50).”
Background
Metadata
- Authors
- Maston, G. A., Evans, S. K., & Green, M. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Annual Review of Genomics and Human Genetics
- Publisher
- Annual Reviews
- Published
- 2006-09-01
- Volume
- 7
- Issue
- 1
- Pages
- 29-59
- ISSN
- 1527-8204 (ISSN-L)
- 1545-293X
- OpenAlex
- W2159164310
- Cited by
- 937
- References
- 202
- Citations by year
- 2026: 18 · 2025: 45 · 2024: 45 · 2023: 39 · 2022: 51 · 2021: 57 · 2020: 57 · 2019: 55 · 2018: 55 · 2017: 45 · 2016: 51 · 2015: 59 · 2014: 61 · 2013: 72 · 2012: 54
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Genomics and Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Human Genome Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- transcriptional regulatory elements, core promoter, proximal promoter, distal enhancers, silencers, insulators, locus control region, general transcription factors, transcriptional activator, transcriptional coactivator, gene expression regulation, human genome annotation
- MeSH terms
- Gene Expression Regulation, Humans, Transcription Factors, Genome, Human, Regulatory Elements, Transcriptional
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