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A unique chromatin signature uncovers early developmental enhancers in humans
Open accessAbstract
Cell-fate transitions involve the integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of genomic sequences that control human embryonic development represents a formidable challenge. Here we show that in human embryonic stem cells (hESCs), unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, monomethylation of histone H3 at lysine 4 (H3K4me1), and low nucleosomal density. In addition, elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized hESC enhancers, and are located proximally to genes expressed in hESCs and the epiblast. In contrast, elements of the second class, which we term 'poised enhancers', are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3), and are linked to genes inactive in hESCs and instead are involved in orchestrating early steps in embryogenesis, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of poised enhancers acquires a chromatin signature associated with active enhancers. When assayed in zebrafish embryos, poised enhancers are able to direct cell-type and stage-specific expression characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that early developmental enhancers are epigenetically pre-marked in hESCs and indicate an unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the wealth of new regulatory sequences identified here provides an invaluable resource for studies and isolation of transient, rare cell populations representing early stages of human embryogenesis.
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“The TRIM33-occupied regions upstream of Bim and Atp1b3 were enriched for H3K27 acetylation but not for H3K4 tri-methylation, suggesting that these elements are active enhancers”
From The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer (2015) · cites this paper as Rada-Iglesias et al., 2011
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“Since H3K27ac modification reliably marks active enhancers located in the distal regions of a given gene, 34”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [34]
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“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 [135]
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“Previous studies suggested that higher levels and a bimodal distribution pattern of monomethylated histone 3 lysine 4 (H3K4me1) correlate with enhancer function (Hoffman et al., 2010; Rada-Iglesias et al., 2011).”
From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Rada-Iglesias et al., 2011
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“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 [135]
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“We inhibited p300 catalytic activity with the small molecule A48530, but did not observe a decrease in TF binding (Fig. 2N–O vs. Fig. 2B–C) or nucleosome occupancy (Fig. S3M), despite a marked reduction in H3K27 acetylation (Fig. S3N)”
From Single-molecule states link transcription factor binding to gene expression (2024) · cites this paper as [30]
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Metadata
- Authors
- Rada-Iglesias, A., Bajpai, R., Swigut, T., Brugmann, S. A., Flynn, R. A., & Wysocka, J.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Wysocka, Joanna
- Venue
- Nature
- Published
- 2010-12-15
- Volume
- 470
- Issue
- 7333
- Pages
- 279-283
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4445674
- OpenAlex
- W2154746182
- Cited by
- 2,233
- References
- 39
- Citations by year
- 2026: 70 · 2025: 108 · 2024: 118 · 2023: 134 · 2022: 117 · 2021: 154 · 2020: 162 · 2019: 144 · 2018: 151 · 2017: 158 · 2016: 154 · 2015: 181 · 2014: 190 · 2013: 185 · 2012: 140
- FWCI
- 50.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Dental and Craniofacial Research (K99DE019853)
- 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 › Pluripotent Stem Cells Research
- Keywords
- enhancers, poised enhancers, human embryonic stem cells, chromatin signatures, H3K4me1, H3K27ac, H3K27me3, P300, SMARCA4, nucleosome density, epiblast, neuroectoderm differentiation, gastrulation, mesoderm formation, neurulation
- MeSH terms
- Acetylation, Animals, Cell Differentiation, Cell Line, Chromatin, DNA Helicases, Enhancer Elements, Genetic, Germ Layers, Histones, Humans, Lysine, Mesoderm, Methylation, Nuclear Proteins, RNA, Transcription Factors, Zebrafish, Gene Expression Regulation, Developmental, Epigenesis, Genetic, Embryonic Development, Chromatin Immunoprecipitation, p300-CBP Transcription Factors, Embryonic Stem Cells, Neural Plate, Neurulation, Gastrulation
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