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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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“Although studies of the characteristics and function of distal regulatory sequences within their endogenous loci are becoming more frequent, most often such elements have been defined in artificial gain-of-function assays, which have revealed distinct classes of regulatory sequences (Maston et al., 2006).”
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“This is because they can be located at a great genomic distance from the target’s transcription start site(s) and can be found upstream, downstream, or within introns (for review, see Maston et al. 2006).”
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“The transcription of eukaryotic genes is an intricate process that requires many protein complexes to interact precisely with these DNA elements [2].”
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BackgroundChromatin interaction analyses elucidate the roles of PRC2-bound silencers in mouse development
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“Spatiotemporal regulation of gene transcription during development is primarily accomplished by enhancers, although those located close to core promoters are also often termed proximal promoters (16).”
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“Such long-range regulatory interactions are emerging as important determinants of tissue-specific expression (4,7,8) and for interpretation of regulatory variation (9,10).”
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“F or p er so na l u se o nl y. machinery at core promoters (Maston et al. 2006).”
BackgroundIn silico prediction of high-resolution Hi-C interaction matrices
Zhang, S., Chasman, D. A., Knaack, S., & Roy, S. (2019) · Nature Communications · doi:10.1038/s41467-019-13423-8 · Cited by 119
A Brief Review on the Human Encyclopedia of DNA Elements (ENCODE) Project
Qu, H., & Fang, X. (2013) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2013.05.001 · Cited by 124
“Many eukaryotic genes are coregulated by multiple TFs in a cell-type specific manner [21].”
BackgroundChromatin-Driven Behavior of Topologically Associating Domains
Ciabrelli, F., & Cavalli, G. (2014) · Journal of Molecular Biology · doi:10.1016/j.jmb.2014.09.013 · Cited by 123
“Enhancer function is usually independent on orientation and distance to the target promoter [45] and can be located upstream, downstream or in intronic regions [30].”
BackgroundIn the loop: promoter–enhancer interactions and bioinformatics
Mora, A., Sandve, G. K., Gabrielsen, O. S., & Eskeland, R. (2015) · Briefings in Bioinformatics · doi:10.1093/bib/bbv097 · Cited by 126
“The proximal promoter encompasses the region immediately upstream (up to a few 100 bp) from the core promoter [149], although arbitrary distance cut-offs are often seen.”
BackgroundWhat does our genome encode?Preprint
Stamatoyannopoulos, J. A. (2012) · Genome Research · doi:10.1101/gr.146506.112 · Cited by 120
“A similar situation obtains in the case of enhancers—classically, elements that mediate transcriptional up-regulation, frequently acting at considerable distance from their target gene(s) (Maston et al. 2006).”
BackgroundGenome-wide discovery of human heart enhancersPreprint
Narlikar, L., Sakabe, N. J., Blanski, A. A., Arimura, F. E., Westlund, J. M., Nóbrega, M. A., & Ovcharenko, I. (2010) · Genome Research · doi:10.1101/gr.098657.109 · Cited by 121
Promoter analysis and prediction in the human genome using sequence-based deep learning models
Umarov, R. K., Kuwahara, H., Li, Y., Gao, X., & Solovyev, V. V. (2018) · Bioinformatics · doi:10.1093/bioinformatics/bty1068 · Cited by 120
“One explanation for this is that such complex and diverse structures must be “designed” to properly control expression of (cid:24) 25,000 protein coding genes based on interactions with only (cid:24) 1,850 transcription factors in the human genome (Maston et al. , 2006).”
BackgroundCis-regulatory mutations in human disease
Epstein, D. J. (2009) · Briefings in Functional Genomics and Proteomics · doi:10.1093/bfgp/elp021 · Cited by 117
“CIS-REGULATIONOF GENE EXPRESSION The transcription of RNA polymerase II (Pol II)dependent genes is mediated by the recruitment of general and sequence-specific transcription factors to cis-acting regulatory sequences including core and proximal promoter elements that reside within 1 kb of the transcription start site…”
BackgroundIdentifying regulatory elements in eukaryotic genomes
Narlikar, L., & Ovcharenko, I. (2009) · Briefings in Functional Genomics and Proteomics · doi:10.1093/bfgp/elp014 · Cited by 122
“Multiple other promoter mutations have been also associated with different diseases [5].”
BackgroundRegulatory variants: from detection to predicting impact
Rojano, E., Seoane, P., Ranea, J. A. G., & Perkins, J. R. (2018) · Briefings in Bioinformatics · doi:10.1093/bib/bby039 · Cited by 120
Chromatin and epigenetic features of long-range gene regulation
Harmston, N., & Lenhard, B. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt499 · Cited by 113
“Traditionally, they are thought to act independently of both the distance and orientation relative to the promoter (18), although some have challenged this assumption (19).”
BackgroundGheldof, N., Smith, E. M., Tabuchi, T. M., Koch, C. M., Dunham, I., Stamatoyannopoulos, J. A., & Dekker, J. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq175 · Cited by 114
“In addition, these sequences are often conserved across species (8,9).”
Predicting enhancers with deep convolutional neural networks
Xu, M., Zeng, W., Chen, S., Chen, N., Chen, T., & Jiang, R. (2017) · BMC Bioinformatics · doi:10.1186/s12859-017-1878-3 · Cited by 107
“…in a cis-acting and tissue specific manner, making these short sequences crucial in the understanding of gene regulatory mechanisms, and thus receiving more and more attentions in not only genomic and epigenomic studies but also the deciphering of genetic basis of human inherited diseases [1 – 3].”
BackgroundNew approaches for genome assembly and scaffolding
Rice, E. S., & Green, R. E. (2019) · Annual Review of Animal Biosciences · doi:10.1146/annurev-animal-020518-115344 · Cited by 110
“Cis-regulation of gene expression can be affected over large genomic distances, such as with interactions between enhancers and promoters, which can be more than 1 Mb apart on a chromosome (46, 47).”
BackgroundHelper T‐cell identity and evolution of differential transcriptomes and epigenomes
Vahedi, G., Poholek, A. C., Hand, T. W., Laurence, A. D. J., Kanno, Y., O’Shea, J. J., & Hirahara, K. (2013) · Immunological Reviews · doi:10.1111/imr.12037 · Cited by 112
Pharmacogenomics in Alzheimer's Disease
Cacabelos, R. (2008) · Methods in molecular biology · doi:10.1007/978-1-59745-205-2_10 · Cited by 109
MPRAnalyze: statistical framework for massively parallel reporter assays
Ashuach, T., Fischer, D. S., Kreimer, A., Ahituv, N., Theis, F. J., & Yosef, N. (2019) · Genome biology · doi:10.1186/s13059-019-1787-z · Cited by 105
Integrative genomic analysis reveals widespread enhancer regulation by p53 in response to DNA damage
Younger, S. T., Kenzelmann-Broz, D., Jung, H., Attardi, L. D., & Rinn, J. L. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv284 · Cited by 99
Engineering Promoter Architecture in Oleaginous Yeast Yarrowia lipolytica
Hussain, M. S., Gambill, L., Smith, S., & Blenner, M. (2015) · ACS Synthetic Biology · doi:10.1021/acssynbio.5b00100 · Cited by 104
Bansal, M., Kumar, A. A., & Yella, V. R. (2014) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2014.01.007 · Cited by 107
Fang, L., Liu, S., Liu, M., Kang, X., Lin, S., Li, B., Connor, E. E., Baldwin, R. L., Tenesa, A., Ma, L., et al. (2019) · BMC Biology · doi:10.1186/s12915-019-0687-8 · Cited by 103
A recellularized human colon model identifies cancer driver genes
Chen, H. J., Wei, Z., Sun, J. M., Bhattacharya, A., Savage, D. J., Serda, R. E., Mackeyev, Y., Curley, S. A., Bu, P., Wang, L., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3586 · Cited by 99
“We mapped these clonal insertion sites in each sample to the human genome annotation file, RefGene, and picked the sites that were located within 1000 bp of known transcripts in RefGene to cover both the core promoter and proximal promoter elements [48].”
MethodA chromosome inversion near the KIT gene and the Tobiano spotting pattern in horses
Brooks, S. A., Lear, T. L., Adelson, D. L., & Bailey, E. (2007) · Cytogenetic and Genome Research · doi:10.1159/000112065 · Cited by 101
“Regulatory gene elements that form a loop structure, like enhancers, insulators, and locus control regions, can bind sequences both upstream and downstream of their target gene (Maston et al., 2006).”
BackgroundReynolds, R. H., Botía, J. A., Nalls, M. A., Noyce, A. J., Nicolas, A., Cookson, M., Bandrés‐Ciga, S., Gibbs, J. R., Hernandez, D. G., Singleton, A., et al. (2019) · npj Parkinson s Disease · doi:10.1038/s41531-019-0076-6 · Cited by 101
Promoter-Enhancer Communication Occurs Primarily within Insulated Neighborhoods
Sun, F., Chronis, C., Kronenberg, M., Chen, X., Su, T., Lay, F. D., Plath, K., Kurdistani, S. K., & Carey, M. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.10.039 · Cited by 94
“Promoter-enhancer deletion studies established long ago that a transcription factor-bound proximal promoter is necessary for the enhancer to function on a gene (Maston et al., 2006).”
BackgroundCharacterization of Enhancer Function from Genome-Wide Analyses
Maston, G. A., Landt, S. G., Snyder, M. P., & Green, M. R. (2012) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-090711-163723 · Cited by 105
Self-citationProgress and challenges in bioinformatics approaches for enhancer identification
Kleftogiannis, D., Kalnis, P., & Bajić, V. B. (2015) · Briefings in Bioinformatics · doi:10.1093/bib/bbv101 · Cited by 92
“th e A U C co m p ar ed w it h st at eo fth ear t H M M ba se d m et h o d s – [3 2]”
BackgroundInfluentialManagement of Gene Promoter Mutations in Molecular Diagnostics
de Vooght, K. M. K., van Wijk, R., & van Solinge, W. W. (2009) · Clinical Chemistry · doi:10.1373/clinchem.2008.120931 · Cited by 94
ChIA-PET analysis of transcriptional chromatin interactions
Zhang, J., Poh, H. M., Peh, S. Q., Sia, Y. Y., Li, G., Mulawadi, F. H., Goh, Y., Fullwood, M. J., Sung, W.-K. K., Ruan, X., et al. (2012) · Methods · doi:10.1016/j.ymeth.2012.08.009 · Cited by 96
Scranton, M. A., Ostrand, J. T., Georgianna, D. R., Lofgren, S., Li, D. D., Ellis, R. C., Carruthers, D. N., Dräger, A., Masica, D. L., & Mayfield, S. P. (2016) · Algal Research · doi:10.1016/j.algal.2016.02.011 · Cited by 93
Clinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders
Vincent, M., Karolak, J. A., Deutsch, G. H., Gambin, T., Popek, E. J., Isidor, B., Szafrański, P., Caignec, C. L., & Stankiewicz, P. (2019) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201903-0495tr · Cited by 92
“within promoters, enhancers, or silencers are well known to control gene activity (81).”
BackgroundEmergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations
Zhou, S., Treloar, A. E., & Lupien, M. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0745 · Cited by 89
“These cis-regulatory elements are directly involved in modulating gene expression and noncoding RNA transcription through long-range chromatin interactions (Figure 1A–D) (7,8).”
BackgroundDetailing regulatory networks through large scale data integration
Huttenhower, C., Mutungu, K. T., Indik, N., Yang, W., Schroeder, M., Forman, J. J., Troyanskaya, O. G., & Coller, H. A. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp588 · Cited by 90
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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