Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation
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Monomethylation of histone H3 at lysine 4 (H3K4me1) and acetylation of histone H3 at lysine 27 (H3K27ac) are correlated with transcriptionally engaged enhancer elements, but the functional impact of these modifications on enhancer activity is not well understood. Here we used CRISPR/Cas9 genome editing to separate catalytic activity-dependent and independent functions of Mll3 (Kmt2c) and Mll4 (Kmt2d, Mll2), the major enhancer H3K4 monomethyltransferases. Loss of H3K4me1 from enhancers in Mll3/4 catalytically deficient cells causes partial reduction of H3K27ac, but has surprisingly minor effects on transcription from either enhancers or promoters. In contrast, loss of Mll3/4 proteins leads to strong depletion of enhancer Pol II occupancy and eRNA synthesis, concomitant with downregulation of target genes. Interestingly, downregulated genes exhibit reduced polymerase levels in gene bodies, but not at promoters, suggestive of pause-release defects. Altogether, our results suggest that enhancer H3K4me1 provides only a minor contribution to the long-range coactivator function of Mll3/4.
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Many enhancer-associated biochemical features may have nothing to do with the enhancers' mechanism of action.
“Fourth, many enhancer-associated biochemical features may have nothing to do with the enhancers’ mechanism of action.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [80]
The Discussion (page not available in our copy) finds that H3K4me1, a canonical enhancer-associated mark, has only a minor effect on maintaining enhancer activity in mouse embryonic stem cells. This supports the possibility that an associated feature need not drive enhancer function, but the paper does not establish that many biochemical features are unrelated to enhancers’ mechanisms of action; it also leaves open roles for H3K4me1 in other contexts. (LLM, conf=0.84)
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- Authors
- Dorighi, K. M., Swigut, T., Henriques, T., Bhanu, N. V., Scruggs, B. S., Nady, N., Still, C. D., Garcia, B. A., Adelman, K., & Wysocka, J.
- Affiliations
- Stanford Medicine (US)
- National Institutes of Health (US)
- University of Pennsylvania (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wysocka, Joanna
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 66
- Issue
- 4
- Pages
- 568-576.e4
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5662137
- OpenAlex
- W2611717200
- Cited by
- 403
- References
- 49
- Citations by year
- 2026: 28 · 2025: 31 · 2024: 38 · 2023: 49 · 2022: 53 · 2021: 46 · 2020: 60 · 2019: 45 · 2018: 41 · 2017: 12
- FWCI
- 17.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute, NIH (R01 GM112720)
- March of Dimes Foundation
- NIGMS IRACDA K12 award
- Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES101987)
- NIH (GM110174, CA196539)
- Leukemia and Lymphoma Society Robert Arceci Scholar award
- 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
- MLL3, KMT2D, H3K4 monomethylation, H3K4me1, enhancer-promoter interactions, H3K27 acetylation, RNA polymerase II occupancy, histone methyltransferase
- MeSH terms
- Gene Editing, Animals, Cell Line, DNA-Binding Proteins, Enhancer Elements, Genetic, Histones, Male, Methylation, Mutation, Promoter Regions, Genetic, Histone-Lysine N-Methyltransferase, RNA, Time Factors, Transcription, Genetic, Transfection, Transcriptional Activation, Gene Expression Regulation, Developmental, Mice, Embryonic Stem Cells, CRISPR-Cas Systems
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