Genome-wide relationship between histone H3 lysine 4 mono- and tri-methylation and transcription factor binding
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We characterized the relationship of H3K4me1 and H3K4me3 at distal and proximal regulatory elements by comparing ChIP-seq profiles for these histone modifications and for two functionally different transcription factors: STAT1 in the immortalized HeLa S3 cell line, with and without interferon-gamma (IFNG) stimulation; and FOXA2 in mouse adult liver tissue. In unstimulated and stimulated HeLa cells, respectively, we determined ∼270,000 and ∼301,000 H3K4me1-enriched regions, and ∼54,500 and ∼76,100 H3K4me3-enriched regions. In mouse adult liver, we determined ∼227,000 and ∼34,800 H3K4me1 and H3K4me3 regions. Seventy-five percent of the ∼70,300 STAT1 binding sites in stimulated HeLa cells and 87% of the ∼11,000 FOXA2 sites in mouse liver were distal to known gene TSS; in both cell types, ∼83% of these distal sites were associated with at least one of the two histone modifications, and H3K4me1 was associated with over 96% of marked distal sites. After filtering against predicted transcription start sites, 50% of ∼26,800 marked distal IFNG-stimulated STAT1 binding sites, but 95% of ∼5800 marked distal FOXA2 sites, were associated with H3K4me1 only. Results for HeLa cells generated additional insights into transcriptional regulation involving STAT1. STAT1 binding was associated with 25% of all H3K4me1 regions in stimulated HeLa cells, suggesting that a single transcription factor can interact with an unexpectedly large fraction of regulatory regions. Strikingly, for a large majority of the locations of stimulated STAT1 binding, the dominant H3K4me1/me3 combinations were established before activation, suggesting mechanisms independent of IFNG stimulation and high-affinity STAT1 binding.
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Active and primed enhancers are marked by H3K4me1 in a cell type-specific manner.
“In mammalian cells, active and primed enhancers are marked by monomethylation of histone 3 (H3) at lysine 4 (K4) (H3K4me1) in a cell type-specific manner.”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [32]
The Abstract (page unavailable) identifies H3K4me1 as a dominant mark of active and potentially active distal regulatory regions, supporting the active-and-primed portion of the claim. It compares HeLa cells with mouse liver and says modification combinations may vary between biological systems, but it does not establish that enhancer marking is cell type-specific. (LLM, conf=0.86)
Experimental — accuracy not yet measuredH3K4me1 and H3K4me3 mark enhancers and promoters respectively.
“In particular, lysine 4 of histone 3 monomethylation (H3K4me1) and trimethylation (H3K4me3) mark enhancers and promoters respectively (15).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [15]
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- Authors
- Robertson, A. G., Bilenky, M., Tam, A., Zhao, Y., Zeng, T., Thiessen, N., Cezard, T., Fejes, A. P., Wederell, E. D., Cullum, R., Euskirchen, G., Krzywinski, M., Birol, I., Snyder, M., Hoodless, P. A., Hirst, M., Marra, M. A., & Jones, S. J. M.
- Affiliations
- BC Cancer Agency (CA)
- Yale University (US)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-09-11
- Volume
- 18
- Issue
- 12
- Pages
- 1906-1917
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC2593584
- OpenAlex
- W2122699308
- Cited by
- 182
- References
- 26
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 2 · 2022: 6 · 2021: 8 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 3 · 2015: 11 · 2014: 14 · 2013: 13 · 2012: 25
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Genome Research (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genome Canada
- Michael Smith Health Research BC
- Genome British Columbia
- 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
- H3K4me1, H3K4me3, histone methylation, transcription factor binding, STAT1, interferon-gamma, FOXA2, liver, distal regulatory elements, transcription start sites, HeLa cells, chromatin regulation, transcriptional regulation
- MeSH terms
- Animals, Base Sequence, Binding Sites, Cell Line, Transformed, Female, Gene Expression Regulation, HeLa Cells, Histones, Humans, Interferon-gamma, Lysine, Methylation, Mice, Inbred C57BL, Protein Binding, Regulatory Sequences, Nucleic Acid, Sequence Homology, Nucleic Acid, Transcription Factors, Genome, Human, Chromatin Immunoprecipitation, STAT1 Transcription Factor, Mice, Hepatocyte Nuclear Factor 3-beta
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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