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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.”
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“The Preinitiation complex, comprised of RNA polymerase II and its auxiliary components (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH) that bound to the core promoter, can only initiate basal levels of transcription [1].”
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“At the base layer of DNA features, the association between DNA regulatory elements, such as TATA box and CpG islands in the promoter regions, and tissuespecific regulation has been investigated experimentally [1] and computationally [4]; Tissue-specific regulatory transcription factor binding sites in the promoter reg…”
BackgroundEnhancer-like long-range transcriptional activation by λ CI-mediated DNA looping
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“Enhancers are usually complex, being composed of multiple DNA elements that bind a variety of proteins (1, 2).”
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“Significant regulation is known to occur at the level of transcriptional initiation and elongation [1], through the combinatorial interactions of transcription factors”
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“It is also known that enhancers usually work with promoters to regulate the expression of genes in a tissue specific way, making these short DNA sequences crucial in the understanding of complicated mechanisms of gene regulation and receiving more and more attentions in modern genomic studies [1]–[3].”
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“The transcription of genes depends on the interaction of their promoter regions with polymerases that synthesize RNA from genomic DNA in combination with an array of regulatory factors (1, 2).”
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“Transcriptional regulation is a complex process, limited not only to cis-acting elements but also to trans-acting elements such as enhancers, silencers, insulators and locus specific regions, and may involve several regions and CpG islands [48] not only in the promoter regions but also other sites in the gene bodies […”
BackgroundEnhancer networks revealed by correlated DNAse hypersensitivity states of enhancers
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“Eukaryotic transcription is intricately regulated at multiple levels, including epigenomic modifications, chromatin reorganization and sequence-specific binding of transcription factor (TF) to either proximal promoter regions or to distal enhancer/repressor regions of a gene (1,2).”
BackgroundAdvances in analysis of transcriptional regulatory networks
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A comprehensive survey on genetic algorithms for DNA motif prediction
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“Conclusions As SNPs may affect the regulation of genes up to 1 Mb away [84], future studies should examine the regulation”
BackgroundCapturing large genomic contexts for accurately predicting enhancer-promoter interactions
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“The gene is transferred to the protein through a sequence of transcription (Maston et al., 2006) and translation (Xiao et al., 2016), and proteins control the organism ’ s exterior phenotypic shape (Buccitelli and Selbach, 2020).”
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Sequence signatures extracted from proximal promoters can be used to predict distal enhancers
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“Both enhancers and promoters have been shown to contain DNA motifs for specific TFs, depending on their tissue-specific activities (for example, [8-10]).”
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Chapter 5 Long‐Range Regulation of α‐Globin Gene Expression
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Functional Validation of a Constitutive Autonomous Silencer Element
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“We focused on p300 because it is a known enhancer-associated co-activator that mediates the regulation of target gene expression (39,40).”
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“binding sites which are more important when found on the proximal promoters form a highly flexible and context-dependent structure [5] for each gene [6-8].”
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BackgroundThe ENCODE project: implications for psychiatric genetics
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“This expressional profile is mediated by the interaction between transcription factors and their sequence-specific binding sites (1).”
BackgroundWSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit
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“The regulation of gene expression by distal elements is complex and includes the activity of enhancer, modulators of chromatin structure, insulators, locus control regions and promoters [91,92].”
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“Gene expression is controlled by carefully orchestrated processes including chromatin rearrangement, transcriptional regulatory elements, and molecular machinery including activators and transcription factors (TFs) (14).”
BackgroundModeling co-occupancy of transcription factors using chromatin features
Liu, L., Zhao, W., & Zhou, X. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1281 · Cited by 27
“TFs tend to work with others for accurately regulating expression of their target genes by binding to the same regulatory regions (16).”
BackgroundYu, S., Liao, J., Tang, M., Wang, Y., Wei, X., Mao, L., Zeng, C., & Wang, G. (2017) · Poultry Science · doi:10.3382/ps/pex217 · Cited by 26
Positional bias of general and tissue-specific regulatory motifs in mouse gene promoters
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“The promoter is often divided into the basal or core promoter, covering approximately 100 bp upstream of the TSS, and the proximal promoter, which extends up to a few hundred base pairs and typically contains multiple sites for activators [1].”
BackgroundDissecting sources of quantitative gene expression pattern divergence between Drosophila species
Wunderlich, Z., Bragdon, M. D. J., Eckenrode, K. B., Lydiard‐Martin, T., Pearl‐Waserman, S., & DePace, A. H. (2012) · Molecular Systems Biology · doi:10.1038/msb.2012.35 · Cited by 23
“Changes in any part of a gene’s regulatory DNA or the expression patterns of the regulatory molecules that bind this DNA can influence a gene’s expression pattern (Maston et al , 2006; Consortium et al , 2010).”
BackgroundEukaryotic and Prokaryotic Gene Structure
Shafee, T. M. A., & Lowe, R. G. T. (2017) · WikiJournal of Medicine · doi:10.15347/wjm/2017.002 · Cited by 34
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Development and antitumor activity of a BCL-2 targeted single-stranded DNA oligonucleotide
Rodrigueza, W. V., Woolliscroft, M. J., Ebrahim, A.-S., Forgey, R. W., McGovren, P. J., Endert, G., Wagner, A., Holewa, D. D., Aboukameel, A., Gill, R. D., et al. (2014) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-014-2476-y · Cited by 27
Sokol, M., Wabl, M. R., Ruiz, I. R., & Pedersen, F. S. (2014) · Retrovirology · doi:10.1186/1742-4690-11-36 · Cited by 25
“While promoters and promoterproximal enhancers are functionally similar [31,32], promoter-distal enhancers may enhance transcription from thousands of bp away.”
BackgroundAltered TERT promoter and other genomic regulatory elements: occurrence and impact
Heidenreich, B., & Kumar, R. (2017) · International Journal of Cancer · doi:10.1002/ijc.30735 · Cited by 26
Transcriptional Regulation of NMDA Receptor Expression
Bai, G., & Hoffman, P. W. (2008) · Frontiers in neuroscience · doi:10.1201/9781420044157.ch5 · Cited by 26
Wang, G., Liao, J., Tang, M., & Yu, S. (2017) · British Poultry Science · doi:10.1080/00071668.2017.1379053 · Cited by 24
“Transcriptional regulatory elements (e.g. core promoters, proximal promoters, distal enhancers, silencers and insulators) and trans-acting factors (general transcription factors, activators and coactivators) play major roles in controlling gene expression (Maston et al. 2006).”
BackgroundCancerEnD: A database of cancer associated enhancers
Kumar, R., Lathwal, A., Kumar, V. D., Patiyal, S., Raghav, P. K., & Raghava, G. P. S. (2020) · Genomics · doi:10.1016/j.ygeno.2020.04.028 · Cited by 24
Experimental evolution supports signatures of sexual selection in genomic divergence
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Pathogenic Mis-splicing of CPEB4 in Schizophrenia
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The physics of protein–DNA interaction networks in the control of gene expression
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“The values of the parameters used in ‘In[7]’ of figure 3 are [24]: e1 = −27.”
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“The three types of distal regulatory elements, including enhancers, silencers and insulators, have been suggested to function in orientation-independent manners [14].”
BackgroundInfluentialPharmacogene regulatory elements: from discovery to applications
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“Insulators create cis-regulatory boundaries that prevent the transcriptional activity of one gene from aff ecting neighboring genes [14,15,119,120].”
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Detection of DNA structural motifs in functional genomic elementsPreprint
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“We chose this size because it represents a reasonable size for the footprint of a DNA-binding factor (Maston et al. 2006).”
BackgroundSmeland, O. B., Kutrolli, G., Bahrami, S., Fominykh, V., Parker, N., Fuhrer, J., Hindley, G., Rødevand, L. N., Jaholkowski, P. P., Tesfaye, M., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02090-2 · Cited by 57
“Gene boundaries were expanded to 35 kb upstream and 10 kb down-stream to include probable regulatory regions outside the transcribed region 85 .”
Regulatory RNAs: A Universal Language for Inter-Domain Communication
Layton, E., Fairhurst, A., Griffiths‐Jones, S., Grencis, R. K., & Roberts, I. S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238919 · Cited by 24
“The expansive non-coding regions of eukaryotic genomes are now known to encode many important regulatory elements such as promoters, enhancers and long non-coding RNAs (lncRNAs) that influence the transcription of both protein-coding and non-coding regions [1,2].”
BackgroundAn overview of transcription in dinoflagellates
Zaheri, B., & Morse, D. (2022) · Gene · doi:10.1016/j.gene.2022.146505 · Cited by 23
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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