Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4
Open accessAbstract
Monomethylation of histone H3 on Lys 4 (H3K4me1) and acetylation of histone H3 on Lys 27 (H3K27ac) are histone modifications that are highly enriched over the body of actively transcribed genes and on enhancers. Although in yeast all H3K4 methylation patterns, including H3K4me1, are implemented by Set1/COMPASS (complex of proteins associated with Set1), there are three classes of COMPASS-like complexes in Drosophila that could carry out H3K4me1 on enhancers: dSet1, Trithorax, and Trithorax-related (Trr). Here, we report that Trr, the Drosophila homolog of the mammalian Mll3/4 COMPASS-like complexes, can function as a major H3K4 monomethyltransferase on enhancers in vivo. Loss of Trr results in a global decrease of H3K4me1 and H3K27ac levels in various tissues. Assays with the cut wing margin enhancer implied a functional role for Trr in enhancer-mediated processes. A genome-wide analysis demonstrated that Trr is required to maintain the H3K4me1 and H3K27ac chromatin signature that resembles the histone modification patterns described for enhancers. Furthermore, studies in the mammalian system suggested a role for the Trr homolog Mll3 in similar processes. Since Trr and mammalian Mll3/4 complexes are distinguished by bearing a unique subunit, the H3K27 demethylase UTX, we propose a model in which the H3K4 monomethyltransferases Trr/Mll3/Mll4 and the H3K27 demethylase UTX cooperate to regulate the transition from inactive/poised to active enhancers.
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MLL4, alongside MLL3, is a histone methyltransferase that establishes H3K4me1/2 at enhancers in mammalian cells.
“Mixed-lineage leukaemia 4 (MLL4, also known as KMT2D), alongside the closely related MLL3 (KMT2C), is a histone methyltransferase that establishes H3K4me1/2 at enhancers in mammalian cells35–37.”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [35]
The section “The mammalian homolog of Trr, Mll3, is also a major monomethyltransferase” reports reduced enhancer-associated H3K4me1 in Mll3-knockout mouse cells; Figure 7C proposes H3K4me1 activity for mammalian Mll3/Mll4 complexes. These passages support the H3K4me1 portion, but not the claim that MLL3 and MLL4 establish H3K4me2 at enhancers. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMLL4 serves as a main H3K4 mono-methyltransferase for enhancer activation and exhibits cell type and differentiation stage specific binding.
“MLL4 serves as a main H3K4 mono-methyltransferase for enhancer activation35,36,38 and exhibits cell type and differentiation stage specific binding37,41.”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [35]
The section 'The mammalian homolog of Trr, Mll3, is also a major monomethyltransferase' reports reduced enhancer-associated H3K4me1 in Mll3-knockout fibroblasts and proposes a role for Mll3/Mll4 complexes in enhancer activation. It does not directly establish that MLL4 itself is a main monomethyltransferase; Mll4's contribution is presented as possible functional redundancy. The cell-type and differentiation-stage binding clause carries different citations, so it is not attributed to this source here. (LLM, conf=0.83)
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References 77 · Cited by 388
Research works printed but not linked: 4
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- Mohan M, Herz HM, Shilatifard A. 2012. SnapShot: Histone lysine methylase complexes. Cell 149: 498-498e1. doi: 10.1016/j.cell.2012.03.025. · DOI
- Vandamme J, Lettier G, Sidoli S, Di Schiavi E, Norregaard Jensen O, Salcini AE. 2012. The C. elegans H3K27 demeth- ylase UTX-1 is essential for normal development, indepen- dent of its enzymatic activity. PLoS Genet 8: e1002647. doi: 10.1371/journal.pgen.1002647. · DOI
- Authors
- Herz, H.-M., Mohan, M., Garruss, A. S., Liang, K., Takahashi, Y.-H., Mickey, K., Voets, O., Verrijzer, C. P., & Shilatifard, A.
- Affiliations
- Stowers Institute for Medical Research (US)
- Erasmus MC (NL)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-11-19
- Volume
- 26
- Issue
- 23
- Pages
- 2604-2620
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3521626
- OpenAlex
- W2150090219
- Cited by
- 388
- References
- 77
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 23 · 2023: 34 · 2022: 21 · 2021: 27 · 2020: 31 · 2019: 23 · 2018: 35 · 2017: 38 · 2016: 30 · 2015: 29 · 2014: 33 · 2013: 24 · 2012: 1
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Funders
- Jane Coffin Childs Memorial Fund for Medical Research
- National Cancer Institute (R01CA150265)
- 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, H3K27 acetylation, enhancers, KDM6A, H3K27 demethylation, enhancer activation, Drosophila, histone modifications, chromatin regulation
- MeSH terms
- Animals, Cell Line, Drosophila melanogaster, Enhancer Elements, Genetic, Histones, Methylation, Histone-Lysine N-Methyltransferase, Drosophila Proteins, Genome-Wide Association Study
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