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The transcription factor Grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes
Open accessAbstract
Transcriptional enhancers function as docking platforms for combinations of transcription factors (TFs) to control gene expression. How enhancer sequences determine nucleosome occupancy, TF recruitment and transcriptional activation in vivo remains unclear. Using ATAC-seq across a panel of Drosophila inbred strains, we found that SNPs affecting binding sites of the TF Grainy head (Grh) causally determine the accessibility of epithelial enhancers. We show that deletion and ectopic expression of Grh cause loss and gain of DNA accessibility, respectively. However, although Grh binding is necessary for enhancer accessibility, it is insufficient to activate enhancers. Finally, we show that human Grh homologs-GRHL1, GRHL2 and GRHL3-function similarly. We conclude that Grh binding is necessary and sufficient for the opening of epithelial enhancers but not for their activation. Our data support a model positing that complex spatiotemporal expression patterns are controlled by regulatory hierarchies in which pioneer factors, such as Grh, establish tissue-specific accessible chromatin landscapes upon which other factors can act.
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“Thus, a potentially large fraction of accessible regions, as captured by scATAC-seq, may not represent functional enhancers.”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [9]
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“The mechanisms of pioneer factor action are still being established [37], but at least some of them (such as FOXA, OCT4 and SOX2/SOX11) have been shown to initiate chromatin opening by direct displacement of histones [38–41], whilst many others recruit chromatin remodelers [42–50].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [41]
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“However, chromatin accessibility is not necessarily always associated with enhancer activity35.”
From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [35]
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“chromatin accessibility is necessary but not sufficient for activity9.”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [9]
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“chromatin accessibility is not necessarily always associated with enhancer activity9.”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [9]
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Metadata
- Authors
- Jacobs, J., Atkins, M., Davie, K., Imrichova, H., Romanelli, L., Christiaens, V., Hulselmans, G., Potier, D., Wouters, J., Taskiran, I. I., Paciello, G., González-Blas, C. B., Koldere, D., Aibar, S., Halder, G., & Aerts, S.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Boğaziçi University (TR)
- Politecnico di Torino (IT)
- Corresponding author
- Aerts, Stein
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-06-04
- Volume
- 50
- Issue
- 7
- Pages
- 1011-1020
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6031307
- OpenAlex
- W2806844404
- Cited by
- 155
- References
- 98
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 22 · 2023: 15 · 2022: 23 · 2021: 17 · 2020: 28 · 2019: 16 · 2018: 8
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Lirias (submittedVersion, other-oa)
- Funders
- National Institutes of Health (P40OD018537)
- 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
- transcription factors, enhancer accessibility, nucleosome displacement, pioneer factors, chromatin accessibility, GRHL1, GRHL2, GRHL3, Drosophila, transcriptional activation, regulatory hierarchy, tissue-specific gene expression, single nucleotide polymorphisms
- MeSH terms
- Animals, Binding Sites, Chromatin, DNA-Binding Proteins, Drosophila melanogaster, Enhancer Elements, Genetic, Epithelial Cells, Humans, Nucleosomes, Transcription Factors, Transcriptional Activation, Gene Expression Regulation, Developmental, Polymorphism, Single Nucleotide, Drosophila Proteins, Animals, Genetically Modified, Cell Line, Tumor, MCF-7 Cells
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