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Transcriptional cofactors display specificity for distinct types of core promoters
Open accessAbstract
Transcriptional cofactors (COFs) communicate regulatory cues from enhancers to promoters and are central effectors of transcription activation and gene expression 1. Although some COFs have been shown to prefer certain promoter types 2-5 over others (for example, see refs 6,7), the extent to which different COFs display intrinsic specificities for distinct promoters is unclear. Here we use a high-throughput promoter-activity assay in Drosophila melanogaster S2 cells to screen 23 COFs for their ability to activate 72,000 candidate core promoters (CPs). We observe differential activation of CPs, indicating distinct regulatory preferences or 'compatibilities'8,9 between COFs and specific types of CPs. These functionally distinct CP types are differentially enriched for known sequence elements 2,4, such as the TATA box, downstream promoter element (DPE) or TCT motif, and display distinct chromatin properties at endogenous loci. Notably, the CP types differ in their relative abundance of H3K4me3 and H3K4me1 marks (see also refs 10-12), suggesting that these histone modifications might distinguish trans-regulatory factors rather than promoter- versus enhancer-type cis-regulatory elements. We confirm the existence of distinct COF-CP compatibilities in two additional Drosophila cell lines and in human cells, for which we find COFs that prefer TATA-box or CpG-island promoters, respectively. Distinct compatibilities between COFs and promoters can explain how different enhancers specifically activate distinct sets of genes 9, alternative promoters within the same genes, and distinct transcription start sites within the same promoter 13. Thus, COF-promoter compatibilities may underlie distinct transcriptional programs in species as divergent as flies and humans.
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“Enhancers regulating housekeeping genes may act via a distinct sets of TFs and cofactors than enhancers regulating developmentally specific genes79,120.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [120]
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Metadata
- Authors
- Haberle, V., Arnold, C. D., Pagani, M., Rath, M., Schernhuber, K., & Stark, A.
- Affiliations
- Research Institute of Molecular Pathology (AT)
- Corresponding author
- Stark, Alexander
- Venue
- Nature
- Published
- 2019-05-15
- Volume
- 570
- Issue
- 7759
- Pages
- 122-126
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7613045
- OpenAlex
- W2945999435
- Cited by
- 123
- References
- 53
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 20 · 2023: 20 · 2022: 25 · 2021: 22 · 2020: 18 · 2019: 8
- FWCI
- 6.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- transcriptional cofactors, core promoter, promoter specificity, enhancer-promoter interactions, transcriptional activation, H3K4me3, H3K4me1, histone modifications, TATA box, downstream promoter element, CpG islands, alternative promoters, transcription start sites, Drosophila melanogaster
- MeSH terms
- Animals, Cell Line, Chromatin, Drosophila melanogaster, Enhancer Elements, Genetic, Histones, Humans, Promoter Regions, Genetic, Substrate Specificity, Transcription Factors, Transcription, Genetic, Transcriptional Activation, TATA Box, CpG Islands, Transcription Initiation Site
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