Histone H3K27ac separates active from poised enhancers and predicts developmental state
Open accessAbstract
Developmental programs are controlled by transcription factors and chromatin regulators, which maintain specific gene expression programs through epigenetic modification of the genome. These regulatory events at enhancers contribute to the specific gene expression programs that determine cell state and the potential for differentiation into new cell types. Although enhancer elements are known to be associated with certain histone modifications and transcription factors, the relationship of these modifications to gene expression and developmental state has not been clearly defined. Here we interrogate the epigenetic landscape of enhancer elements in embryonic stem cells and several adult tissues in the mouse. We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements containing H3K4me1 alone. This indicates that the amount of actively used enhancers is lower than previously anticipated. Furthermore, poised enhancer networks provide clues to unrealized developmental programs. Finally, we show that enhancers are reset during nuclear reprogramming.
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The upstream region of Tet2 is an enhancer element that becomes active upon TLR-4 activation.
“providing support for the upstream region being an enhancer element that becomes active upon TLR-4 activation (Creyghton et al., 2010).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Creyghton et al., 2010
The Results (p. 5) describe enhancers poised to become active after an inflammatory stimulus, and the paper identifies H3K27ac as a marker distinguishing active from poised enhancers (p. 2). Our copy does not identify the upstream Tet2 region as an enhancer or show that it becomes active upon TLR-4 activation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredH3K4me1, associated with the binding of Trithorax/MLL complexes, is taken to be the hallmark of both primed and active enhancers, whilst active enhancers additionally tend to associate with H3K27ac.
“Currently mono-methylation of histone H3 lysine 4 (H3K4me1), associated with the binding of Trithorax/MLL complexes, is taken to be the hallmark of both ‘primed’ and active enhancers, whilst active enhancers additionally tend to associate with the acetylation of histone H3 lysine 27 (H3K27ac) [133–137].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [133]
The introduction (p. 2) says H3K4me1 can mark both active and poised enhancers, and the Results (p. 3) identify H3K27ac as a mark that distinguishes active from poised enhancers. Our copy does not support the additional claim that H3K4me1 is associated with binding of Trithorax/MLL complexes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn the cerebral cortex, rs1057233- and rs78245530-harboring regions exhibited enhancer activity.
“In the cerebral cortex, rs1057233- and rs78245530-harboring regions exhibited enhancer activity (indicated by the low H3K4me3 signal and high H3K27ac signal [45]) (Fig. 2d).”
From Association of SPI1 haplotypes with altered SPI1 gene expression and Alzheimer’s disease risk (2022) · cites this paper as [45]
H3K4me1 in combination with H3K27ac designates the active enhancer state, while H3K4me1 alone, or with H3K27me3, defines a primed or repressed enhancer, respectively.
“Monomethylation on H3K4 (H3K4me1) in combination with acetylation of H3 at K27 (H3K27ac) designates the active enhancer state33 while H3K4me1 alone, or with trimethylation of H3K27 (H3K27me3), defines a primed or repressed enhancer, respectively30.”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [33]
Assisted loading events are coupled with increases in enhancer activity as measured by DNase hypersensitivity or H3K27 acetylation (H3K27ac).
“Assisted loading events are coupled with increases in enhancer activity as measured by DNase hypersensitivity or H3K27 acetylation (H3K27ac), two well-established markers for active enhancers38–40.”
From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [39]
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“For instance, the histone acetyltransferase p300 has been used as a reliable marker to identify distal enhancers (10, 11, 16) and in agreement with this could be found associated with a significant portion of H3K4me1-enriched regions (Fig.”
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- Authors
- Creyghton, M. P., Cheng, A. W., Welstead, G. G., Kooistra, T., Carey, B. W., Steine, E. J., Hanna, J., Lodato, M. A., Frampton, G. M., Sharp, P. A., Boyer, L. A., Young, R. A., & Jaenisch, R.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Jaenisch, Rudolf
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-11-24
- Volume
- 107
- Issue
- 50
- Pages
- 21931-21936
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3003124
- OpenAlex
- W1981030303
- Cited by
- 4,302
- References
- 6
- Citations by year
- 2026: 228 · 2025: 286 · 2024: 349 · 2023: 365 · 2022: 345 · 2021: 362 · 2020: 346 · 2019: 315 · 2018: 292 · 2017: 267 · 2016: 261 · 2015: 242 · 2014: 239 · 2013: 220 · 2012: 124
- FWCI
- 51.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health (2r01ca084198-10)
- U.S. Public Health Service (5-RO1-HDO45022)
- National Human Genome Research Institute (HG002668, R01HG002668)
- National Cancer Institute (R01-CA084198, R01CA087869, 5-RO1-CA87869, P01CA042063, R37CA084198, P30CA014051, P30-CA-14051, P01 CA 42063)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD045022)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- enhancer activity, poised enhancers, H3K4me1, developmental state, embryonic stem cells, nuclear reprogramming, cell differentiation, chromatin regulation, mouse tissues
- MeSH terms
- Acetylation, Animals, Cell Differentiation, Cell Line, Enhancer Elements, Genetic, Histones, Mice, Inbred C57BL, Gene Expression Regulation, Developmental, Mice
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