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Cited by 422Genomics and Chromatin DynamicsEpigenetics and DNA MethylationChromatin Remodeling and Cancer

H3K4me3 regulates RNA polymerase II promoter-proximal pause-release

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Wang, Hua, Fan, Zheng, Shliaha, Pavel V., Miele, Matthew, Hendrickson, Ronald C., Jiang, Xuejun, Helin, Kristian·2023·Nature
DOI 10.1038/s41586-023-05780-8PMC PMC9995272
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Abstract

Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and has been proposed to regulate transcription initiation 1,2 . However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate the elucidation of the specific role of H3K4me3 in transcriptional regulation 3,4 . Here, using mouse embryonic stem cells as a model system, we show that acute ablation of shared subunits of the SET1/COMPASS complexes leads to a complete loss of all H3K4 methylation. Turnover of H3K4me3 occurs more rapidly than that of H3K4me1 and H3K4me2 and is dependent on KDM5 demethylases. Notably, acute loss of H3K4me3 does not have detectable effects on transcriptional initiation but leads to a widespread decrease in transcriptional output, an increase in RNA polymerase II (RNAPII) pausing and slower elongation. We show that H3K4me3 is required for the recruitment of the integrator complex subunit 11 (INTS11), which is essential for the eviction of paused RNAPII and transcriptional elongation. Thus, our study demonstrates a distinct role for H3K4me3 in transcriptional pause-release and elongation rather than transcriptional initiation.

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  • Methylation of H3K9 and H3K27 leads to repressed gene expression, while H3K4 methylation in promoter regions results in relaxed chromatin that promotes gene expression.

    “methylation of H3K9 and H3K27 leads to repressed gene expression;163 while histone methylation of H3K4 in the promoter regions results in relaxed chromatin, which promotes gene expression.164”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [164]

    The Main section says H3K4me3 is enriched at transcription start sites and associated with gene expression; the transcription-results section reports reduced mRNA synthesis after its loss. The paper does not say that H3K4 methylation promotes expression by relaxing chromatin. Its Discussion instead identifies regulation of RNA polymerase II pausing as the demonstrated mechanism. Citation 164 attaches to the H3K4 clause, so the separately cited H3K9/H3K27 clause is not judged here. (LLM, conf=0.88)

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References 60 · Cited by 422

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Authors
Wang, H., Fan, Z., Shliaha, P. V., Miele, M., Hendrickson, R. C., Jiang, X., & Helin, K.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • University of Copenhagen (DK)
Corresponding author
Helin, Kristian
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-03-01
Volume
615
Issue
7951
Pages
339-348
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-05780-8
PMC
PMC9995272
OpenAlex
W4322738638
Cited by
422
References
60
Citations by year
2026: 101 · 2025: 135 · 2024: 140 · 2023: 46
FWCI
38.32
Type
journal article
Language
en
Update notices
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Memorial Sloan-Kettering Cancer Center (CA008748, P30 CA008748, NIH P30CA008748)
  • Novo Nordisk (NNF17CC0027852)
  • Novo Nordisk Fonden (NNF17CC0027852)
  • National Institutes of Health (1s10od010598-01, CA008748, NIH P30 CA008748)
  • National Cancer Institute (R01CA166413, P30CA008748, R01CA258622, R01CA204232)
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
H3K4me3, histone H3 lysine 4 trimethylation, RNA polymerase II, promoter-proximal pausing, transcription elongation, INTS11, Integrator complex, mouse embryonic stem cells, transcriptional output
MeSH terms
Mouse Embryonic Stem Cells, Animals, Endoribonucleases, Gene Expression Regulation, Histones, Methylation, Promoter Regions, Genetic, RNA Polymerase II, Mice, Histone Demethylases, Transcription Elongation, Genetic, Transcription Termination, Genetic

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