Genome-wide characterization of mammalian promoters with distal enhancer functions
Abstract
Gene expression in mammals is precisely regulated by the combination of promoters and gene-distal regulatory regions, known as enhancers. Several studies have suggested that some promoters might have enhancer functions. However, the extent of this type of promoters and whether they actually function to regulate the expression of distal genes have remained elusive. Here, by exploiting a high-throughput enhancer reporter assay, we unravel a set of mammalian promoters displaying enhancer activity. These promoters have distinct genomic and epigenomic features and frequently interact with other gene promoters. Extensive CRISPR-Cas9 genomic manipulation demonstrated the involvement of these promoters in the cis regulation of expression of distal genes in their natural loci. Our results have important implications for the understanding of complex gene regulation in normal development and disease.
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Certain promoters, termed epromoters, can also function as enhancers.
“Finally, evidence from multiple sources including reporter assays [169, 175, 239, 240], CRISPR [240–242], chromatin mapping [243, 244] and population genetics analysis [207, 245] suggests that certain promoters, termed ‘epromoters’, can also function as enhancers (reviewed in [246]).”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [240]
Many epromoters control house-keeping genes in cis as promoters, but may regulate lineage-specific or inducible genes distally as enhancers.
“Notably, while many such elements control house-keeping genes in cis (as promoters), they may regulate lineage-specific or inducible genes distally (as enhancers) [240, 247].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [240]
Promoters can have enhancer activity.
“Now, there is convincing evidence that promoters can have enhancer activity [72,73,74,75], while intragenic enhancers can act as alternative promoters [76].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [72]
Promoters with enhancer activity possess some epigenetic signatures typical for enhancers, such as p300 binding and a high H3K27ac/H3K4me3 ratio.
“Interestingly, promoters with enhancer activity possess some epigenetic signatures typical for enhancers, such as p300 binding and a high H3K27ac/H3K4me3 ratio [72].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [72]
An appreciable number of eQTLs were enriched on the promoter of a different gene from the one regulated, suggesting Epromoter activity.
“an appreciable number of eQTLs were enriched on the promoter of a different gene from the one regulated, suggesting the activity of an Epromoter, a regulatory element with dual promoter and enhancer functions (41).”
From Comprehensive functional genomic resource and integrative model for the human brain (2018) · cites this paper as [41]
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- Authors
- Dao, L. T. M., Galindo-Albarrán, A. O., Castro-Mondragon, J. A., Andrieu-Soler, C., Medina-Rivera, A., Souaid, C., Charbonnier, G., Griffon, A., Vanhille, L., Stephen, T., Alomairi, J., Martin, D., Torres, M., Fernandez, N., Soler, E., van Helden, J., Puthier, D., & Spicuglia, S.
- Affiliations
- Inserm (FR)
- Universidad Nacional Autónoma de México (MX)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Spicuglia, Salvatore
- ORCID
- Venue
- Nature Genetics
- Published
- 2017-06-05
- Volume
- 49
- Issue
- 7
- Pages
- 1073-1081
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2621774891
- Cited by
- 281
- References
- 51
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 28 · 2023: 29 · 2022: 26 · 2021: 31 · 2020: 44 · 2019: 41 · 2018: 35 · 2017: 14
- FWCI
- 15.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-IDEX-0001, ANR-10-INBS-0009)
- 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 › Epigenetics and DNA Methylation
- Keywords
- distal enhancers, enhancer activity, mammalian promoters, enhancer-promoter interactions, gene expression regulation, epigenomic features, CRISPR/Cas9 genome editing
- MeSH terms
- Animals, Enhancer Elements, Genetic, Gene Expression Regulation, HeLa Cells, Humans, Mammals, Promoter Regions, Genetic, 3T3 Cells, Interferon-alpha, K562 Cells, Mice, Epigenomics, Gene Ontology, CRISPR-Cas Systems
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