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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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“It is hypothesized that this regulation process is mainly controlled by the interplay between TFs and their corresponding transcription factor binding sites (TFBSs) on the proximal promoters of the target genes [13,14,15].”
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“Cis-acting regulatory regions include functional elements such as enhancers and insulators [44].”
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“Active regulatory elements are often associated with DNaseI hypersensitive sites (DHS), which are enriched by marks of open chromatin structure and locus accessibility such as histone 3 lysine 4 mono-methylation (H3K4me1) and H3K27 acetylation (H3K27Ac), and contain clusters of transcription factor binding sites (TFBS…”
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“We have not explored the mechanism of this inhibitory effect; however, negative influences of introns on gene expression (49) and mRNA export from the nucleus have been reported previously (50), and one of these mechanisms may be operative here.”
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“Gene boundaries were expanded to 35 kb upstream and 10 kb downstream to include probable regulatory regions outside the transcribed region 89 .”
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“…as enhancers, and transcription factor binding sites, can occur up to 1 Mb up-or downstream from a target gene in other species (Chan et al., 2010; Maston et al., 2006; Pennacchio et al., 2013; Werner et al., 2010) but generally lie within 2 kb of a gene region in D . melanogaster (Arnosti,…”
BackgroundEnhancer-LSTMAtt: A Bi-LSTM and Attention-Based Deep Learning Method for Enhancer Recognition
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“Although several biological elements regulate gene expression, the major contribution is from cis-regulatory elements (CREs) of gene expression, such as promoters, enhancers, and insulators (4).”
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“First, limited by the inherent complexity of gene expression, many potential transcription factors remain unknown to researchers [74,75].”
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“Enhancers can reside several hundred kilobase pairs upstream of a promoter and are well known for their role in activating the transcription of target genes in a time and tissue dependent manner.(20) Despite the considerable amount of data generated from the TRPV1 knockout mouse, there is a paucity of information in h…”
BackgroundThe search for cis-regulatory driver mutations in cancer genomes
Poulos, R. C., Sloane, M. A., Hesson, L. B., & Wong, J. W. H. (2015) · Oncotarget · doi:10.18632/oncotarget.5085 · Cited by 21
“Proximal promoter elements typically lie immediately upstream and within close proximity of the core promoter element [15].”
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“Analysis of motifs is important for advancements of medical treatment and understanding of cell processes [1].”
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“sites are generally situated quite distally from TSSs, while multiple binding sites for activators are located in the promoter [22].”
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“While NREs recruit TFs (repressors), which negatively affect the formation of functional Pol II transcription complexes [37], silencers establish an inheritable repressive chromatin state.”
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“There is precedence for an enhancer being located downstream of its target gene; there is also precedence for an enhancer being located at a distance, up to 100 kb away from the promoter that it controls (Blackwood and Kadonaga, 1998; Carroll et al., 2005; Maston et al., 2006).”
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Towards a map of cis-regulatory sequences in the human genome
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“(Ps ∈Ci ,Pt∈Cj )⊂ dk (Ci ,Cj ) [ o(Ps ,Pt ) |Ps | + o(Ps ,Pt ) |Pt | ] (4)”
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“Of note, methylation in the proximal and distal promoter might have differential effects because of the localization of different transcriptional regulatory elements along the promoter, which in the case of the proximal promoter can be the RNA polymerase binding site, TATA box, and transcription start site, and in the…”
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“THE living and development of organisms are inseparable from the proper function of gene expression in cells, which is regulated by the concerted cooperation of various gene regulatory elements located in the non-coding regions of the genome [1].”
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“Furthermore, disruption of normal regulation has been linked to a number of diseases including hemophilia, anemia, epilepsy, and a variety of cancers [2].”
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“Indeed, disruption of these elements has been linked to a number of human diseases including cancers [1], preaxial polydactyly [2], Van Buchem disease [3], and facioscapulohumeral muscular dystrophy [4].”
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Establishing the Architecture of Plant Gene Regulatory Networks
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“While there are many different types of regulatory elements in the human genome, they can mainly be categorized into four classes: promoters, enhancers, silencers, and insulators (Maston et al. 2006).”
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“Cis-regulatory elements in the upstream of start codons that act as the binding sites of transcription factors are crucial for the transcriptional regulation of protein-coding genes [36].”
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“Exon and intron regions were also enriched in CSREs, suggesting that part of a gene body may serve as regulatory elements, such as enhancers, for its own expression (31).”
BackgroundEpigenomic landscape of enhancer elements during Hydra head organizer formation
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Neuroepigenetic Mechanisms of Action of Ultrashort Peptides in Alzheimer’s Disease
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“Transcriptional regulation is a complicated process that involves the interplay of multiple components (Maston et al. 2006).”
BackgroundDeciphering Combinatorial Genetics
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“A statistical survey on ,10000 predicted human promoter data reveals that among these four promoter elements Inr is the most common and usually occurs about half of the human promoters [3].”
BackgroundMolecular and computational approaches to map regulatory elements in 3D chromatin structure
Lee, B. H., & Rhie, S. K. (2021) · Epigenetics & Chromatin · doi:10.1186/s13072-021-00390-y · Cited by 17
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“Since enhancers are known to be located up to 1Mbp away from their regulatory genes [14, 49], 286 several interceding genes can reside between a TF binding site (peak) in an enhancer and its 287 target gene(s), as modeled by our EnTDefs (Supplementary Figure S6).”
BackgroundZhang, Y., See, Y. X., Tergaonkar, V., & Fullwood, M. J. (2022) · Cells · doi:10.3390/cells11091560 · Cited by 17
“Promoter-distal silencers are usually position and orientation independent and can loop to target promoters to repress gene expression, functioning as the repressive analogue to enhancers [14,15].”
BackgroundShort tandem repeats are important contributors to silencer elements in T cells
Hussain, S., Sadouni, N., van Essen, D., Dao, L. T. M., Ferré, Q., Charbonnier, G., Torres, M., Gallardo, F., Lecellier, C., Sexton, T., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad187 · Cited by 14
Modeling and designing enhancers by introducing and harnessing transcription factor binding units
Li, J., Zhang, P., Xi, X., Liu, L., Wei, L., & Wang, X. (2025) · Nature Communications · doi:10.1038/s41467-025-56749-2 · Cited by 16
Onaolapo, O. J., Onaolapo, A. Y., Olowe, O. A., Udoh, M. O., Udoh, D. O., & Nathaniel, I. T. (2019) · Current Neuropharmacology · doi:10.2174/1570159x18666191230114339 · Cited by 16
Improved detection of motifs with preferential location in promoters
Bernard, V., Lecharny, A., & Brunaud, V. (2010) · Genome · doi:10.1139/g10-042 · Cited by 21
“Approaches combining information on the position relative to the TSS and the frequency of occurrences of a putative regulatory element have been used at the genomic level to characterize promoters (Kiełbasa et al. 2001; FitzGerald et al. 2004; Berendzen et al. 2006; Maston et al. 2006; Bellora et al. 2007; Yamamoto et…”
MethodTerracciano, I., Cantarella, C., Fasano, C., Cardi, T., Mennella, G., & D’Agostino, N. (2017) · Scientific Reports · doi:10.1038/s41598-017-06120-3 · Cited by 16
Transcriptional regulation of metabolism in disease: From transcription factors to epigenetics
Hawkins, L. J., Al-attar, R., & Storey, K. B. (2018) · PeerJ · doi:10.7717/peerj.5062 · Cited by 17
A Glimpse to Background and Characteristics of Major Molecular Biological Networks
Altaf-Ul-Amin, M., Katsuragi, T., Sato, T., & Kanaya, S. (2015) · BioMed Research International · doi:10.1155/2015/540297 · Cited by 15
“Also there are distal regulatory elements, which can be enhancers, silencers, insulators, or locus control regions (LCR) [24].”
BackgroundSokol, M., Jessen, K. M., & Pedersen, F. S. (2015) · Retrovirology · doi:10.1186/s12977-015-0161-9 · Cited by 15
“The promoter regions may contain promoterproximal enhancers and rely on coopted motif usage in case of promoters with diverged nucleotide compositions [42-45].”
BackgroundNiu, M., Tabari, E. S., & Su, Z. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-1047 · Cited by 17
“However, we have had only very limited understanding of transcriptional control elements, particularly promoters, enhancers and silencers in virtually all sequenced large eukaryotic genomes, even though these elements are as important as the transcribed sequences for the functions of an organism [10-12].”
BackgroundFamilial analysis reveals rare risk variants for migraine in regulatory regions
Techlo, T. R., Rasmussen, A., Møller, P. L., Bøttcher, M., Winther, S., Davidsson, O. B., Olofsson, I. A., Chalmer, M. A., Kogelman, L. J. A., Nyegaard, M., et al. (2020) · Neurogenetics · doi:10.1007/s10048-020-00606-5 · Cited by 15
Cheng, Y., & Burt, D. W. (2018) · The International Journal of Developmental Biology · doi:10.1387/ijdb.170276yc · Cited by 16
“…less complex due to their close spatial association (usually within 200 bp) with genes (though can be confounded in the case of multiple transcription start sites), confident annotation of distal elements, such as silencers, enhancers, and insulators, can be difficult (Maston et al., 2006).”
BackgroundPRC2 mediated KLF2 down regulation: a therapeutic and diagnostic axis during tumor progression
Taghehchian, N., Maharati, A., Akhlaghipour, I., Zangouei, A. S., & Moghbeli, M. (2023) · Cancer Cell International · doi:10.1186/s12935-023-03086-3 · Cited by 15
“Transcription factors are the main transcriptional regulators [8].”
BackgroundGene Regulatory Networks: A Primer in Biological Processes and Statistical Modelling
Angelin‐Bonnet, O., Biggs, P. J., & Vignes, M. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-8882-2_15 · Cited by 15
Vastolo, V., Nettore, I. C., Ciccarelli, M., Albano, L., Raciti, G. A., Longo, M., Bèguinot, F., & Ungaro, P. (2018) · Metabolism · doi:10.1016/j.metabol.2018.06.001 · Cited by 15
Gene transcription in the zebrafish embryo: regulators and networks
Ferg, M., Armant, O., Yang, L., Dickmeis, T., Rastegar, S., & Strähle, U. (2013) · Briefings in Functional Genomics · doi:10.1093/bfgp/elt044 · Cited by 17
“in [32, 33]).”
Boyling, A., Pérez‐Siles, G., & Kennerson, M. L. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.842860 · Cited by 15
Two novel DNA motifs are essential for BACE1 gene transcription
Xiang, Y., Meng, S., Wang, J., Li, S., Liu, J., Li, H., Li, T., Song, W., & Zhou, W. (2014) · Scientific Reports · doi:10.1038/srep06864 · Cited by 14
Halfon, M. S., Zhu, Q., Brennan, E. R., & Zhou, Y. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-578 · Cited by 14
“Developmental control of gene expression depends on the activity of transcriptional enhancers, or “cis-regulatory modules” (CRMs) [reviewed by [1,2]].”
BackgroundThe Evolution of Bony Vertebrate Enhancers at Odds with Their Coding Sequence Landscape
Yousaf, A., Raza, M. S., & Abbasi, A. A. (2015) · Genome Biology and Evolution · doi:10.1093/gbe/evv146 · Cited by 14
“Cis-regulatory elements, specifically enhancers, orchestrate gene expression in a spatiotemporal manner during early development (Maston et al. 2006).”
BackgroundWei, Z., Han, C., Li, H., He, W., Zhou, J., Dong, H. F., Wu, Y., Tian, Y., & Luo, G. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00059 · Cited by 14
“Two major mechanisms are involved in gene expression regulation, that is, transcriptional and posttranscriptional regulation (Maston et al., 2006; Chen et al., 2017).”
BackgroundTargeting the Non-Coding Genome for the Diagnosis of Disorders of Sex Development
Atlas, G., Sreenivasan, R., & Sinclair, A. (2021) · Sexual Development · doi:10.1159/000519238 · Cited by 11
“Studies have also shown that multiple enhancers can activate a single promoter, depending on the developmental stage or specific tissue involved [Atchison et al., 1988; Maston et al., 2006].”
BackgroundZhang, T., Li, L., Sun, H., Xu, D., & Wang, G. (2023) · Briefings in Bioinformatics · doi:10.1093/bib/bbad316 · Cited by 14
Hecker, N., Seemann, S. E., Silahtaroglu, A., Ruzzo, W. L., & Gorodkin, J. (2017) · Scientific Reports · doi:10.1038/s41598-017-06200-4 · Cited by 14
Survey of polymorphic sequence variation in the immediate 5′ region of human DNA repair genes
Mohrenweiser, H. W. (2006) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2006.11.008 · Cited by 14
Yang, Z., Zhang, Q., Yu, H., Du, H., Li, L., He, Y., Zhu, S., Li, C., Zhang, S., Luo, B., et al. (2020) · Forensic Science International · doi:10.1016/j.forsciint.2020.110637 · Cited by 13
Neal, A., Nornes, S., Louphrasitthiphol, P., Sacilotto, N., Preston, M. D., Fleisinger, L., Payne, S., & Val, S. D. (2021) · Developmental Biology · doi:10.1016/j.ydbio.2021.01.002 · Cited by 13
“Enhancers, which can be located anywhere within a gene loci and sometimes beyond, are densely clustered groups of transcription factor motifs that bind an array of different transcription factors to activate transcription (Maston et al., 2006).”
BackgroundPattanaik, B., Hammarlund, M. E., Mjörnstedt, F., Ulleryd, M. A., Zhong, W., Uhlén, M., Gummesson, A., Bergström, G., & Johansson, M. E. (2022) · The FASEB Journal · doi:10.1096/fj.202101898r · Cited by 13
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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