Epigenetic signatures distinguish multiple classes of enhancers with distinct cellular functions
Open accessAbstract
Epigenetic regulation of gene enhancer elements is important for establishing and maintaining the identity of cells. Gene enhancer elements are thought to exist in either active or poised states distinguishable by chromatin features, but a complete understanding of the regulation of enhancers is lacking. Here, by using mouse embryonic stem cells and their differentiated derivatives, as well as terminally differentiated cells, we report the coexistence of multiple, defined classes of enhancers that serve distinct cellular functions. Specifically, we found that active enhancers can be subclassified based on varying levels of H3K4me1, H3K27ac, and H3K36me3 and the pSer2/5 forms of RNA polymerase II. The abundance of these histone modifications positively correlates with the expression of associated genes and cellular functions consistent with the identity of the cell type. Poised enhancers can also be subclassified based on presence or absence of H3K27me3 and H3K9me3, conservation, genomic location, expression levels of associated genes, and predicted function of associated genes. These findings not only refine the repertoire of histone modifications at both active and poised gene enhancer elements but also raise the possibility that enhancers associated with distinct cellular functions are partitioned based on specific combinations of histone modifications.
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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 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 [136]
The section ‘Identification of three major enhancer classes in mESCs’ (page not available) classifies H3K4me1-positive, H3K27ac-positive enhancers as active and H3K4me1-positive, H3K27me3-positive enhancers as poised, supporting the histone-mark distinction. Our copy does not establish the claimed association with Trithorax/MLL complexes, and it uses ‘poised’ rather than ‘primed.’ (LLM, conf=0.86)
Experimental — accuracy not yet measuredEnhancers can reside in a poised state exhibiting both H3K4me1 and H3K27me3 that is associated with Polycomb repressive complexes.
“In addition to the ‘primed’ and active states, enhancers can also reside in a ‘poised’ state exhibiting both H3K4me1 and H3 lysine 27 trimethylation (H3K27me3) that is associated with Polycomb repressive complexes [131, 135, 136, 138].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [136]
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- Authors
- Zentner, G. E., Tesar, P. J., & Scacheri, P. C.
- Affiliations
- Case Western Reserve University (US)
- Case Comprehensive Cancer Center (US)
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-06-01
- Volume
- 21
- Issue
- 8
- Pages
- 1273-1283
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC3149494
- OpenAlex
- W2167776710
- Cited by
- 564
- References
- 10
- Citations by year
- 2026: 13 · 2025: 25 · 2024: 17 · 2023: 34 · 2022: 26 · 2021: 46 · 2020: 37 · 2019: 37 · 2018: 34 · 2017: 53 · 2016: 45 · 2015: 58 · 2014: 42 · 2013: 55 · 2012: 33
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute of Mental Health (R33MH087877)
- National Human Genome Research Institute (R01HG004722)
- National Institute of General Medical Sciences (5T32GM008614, 5T32GM008615)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD056369)
- 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
- active enhancers, poised enhancers, histone modifications, H3K4me1, H3K27ac, H3K36me3, H3K27me3, H3K9me3, RNA polymerase II phosphorylation, cell identity, mouse embryonic stem cells, cell differentiation, enhancer function
- MeSH terms
- Animals, Cell Differentiation, Chromatin, Enhancer Elements, Genetic, Germ Layers, Histones, DNA-Directed RNA Polymerases, Gene Expression Profiling, Epigenesis, Genetic, Mice, Embryonic Stem Cells, Neural Stem Cells
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