ArticleGenome biology2023
Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation during embryonic stem cell differentiation.
Article in Genome biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- The H3K4 methyltransferase KMT2D is an essential cofactor for GATA1 at erythroid gene enhancers.Nature communications · 2026Article
- KMT2C Loss Promotes NF2-Wildtype Meningioma Progression and Ferroptosis Sensitivity via Epigenetic Repression of Hippo Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- KMT2C and KMT2D amplify GRHL2-driven enhancer activation.bioRxiv : the preprint server for biology · 2026Article
- In vitro approaches to study centriole and cilium function in early mouse embryogenesis.Life science alliance · 2026Article
- H3K27ac Is Essential for Human Naive Pluripotency Modulated by m6A-Driven EP300 Expression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Epigenetic regulation and maternal-to-zygotic transition in dwarf surf clam (Zoological research · 2025Article
- The exit from naive pluripotency: a platform for the study of enhancer mechanistics.Biochemical Society transactions · 2025Review
- Epigenetic priming of mammalian embryonic enhancer elements coordinates developmental gene networks.Genome biology · 2025Article
- Preliminary investigation of the epigenetic regulation of KMT2D via H3K4me1/H3K27ac in oral squamous cell carcinoma.Cellular and molecular life sciences : CMLS · 2025Article
- Review
- Role and mechanisms of histone methylation in osteogenic/odontogenic differentiation of dental mesenchymal stem cells.International journal of oral science · 2025Review
- NONO interacts with nuclear PKM2 and directs histone H3 phosphorylation to promote triple-negative breast cancer metastasis.Journal of experimental & clinical cancer research : CR · 2025Article
- KMT2C/KMT2D-dependent H3K4me1 mediates changes in DNA replication timing and origin activity during a cell fate transition.Cell reports · 2025Article
- Epigenetic crosstalk between stem cells and tumors: mechanisms and emerging perspectives.American journal of stem cells · 2025Review
- Super-enhancers: drivers of cells' identities and cells' debacles.Epigenomics · 2024Review
- Chromatin modifiers in human disease: from functional roles to regulatory mechanisms.Molecular biomedicine · 2024Review
- Role of H3K4 monomethylation in gene regulation.Current opinion in genetics & development · 2024Review
- Roles and Regulation of H3K4 Methylation During Mammalian Early Embryogenesis and Embryonic Stem Cell Differentiation.Advances in experimental medicine and biology · 2024Review
- MLL3/MLL4 enzymatic activity shapes DNA replication timing.bioRxiv : the preprint server for biology · 2023Article
- SETting up the genome: KMT2D and KDM6A genomic function in the Kabuki syndrome craniofacial developmental disorder.Birth defects research · 2023Review
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
backgroundEnhancers are essential in defining cell fates through the control of cell-type-specific gene expression. Enhancer activation is a multi-step process involving chromatin remodelers and histone modifiers including the monomethylation of H3K4 (H3K4me1) by MLL3 (KMT2C) and MLL4 (KMT2D). MLL3/4 are thought to be critical for enhancer activation and cognate gene expression including through the recruitment of acetyltransferases for H3K27.
resultsHere we test this model by evaluating the impact of MLL3/4 loss on chromatin and transcription during early differentiation of mouse embryonic stem cells. We find that MLL3/4 activity is required at most if not all sites that gain or lose H3K4me1 but is largely dispensable at sites that remain stably methylated during this transition. This requirement extends to H3K27 acetylation (H3K27ac) at most transitional sites. However, many sites gain H3K27ac independent of MLL3/4 or H3K4me1 including enhancers regulating key factors in early differentiation. Furthermore, despite the failure to gain active histone marks at thousands of enhancers, transcriptional activation of nearby genes is largely unaffected, thus uncoupling the regulation of these chromatin events from transcriptional changes during this transition. These data challenge current models of enhancer activation and imply distinct mechanisms between stable and dynamically changing enhancers.
conclusionsCollectively, our study highlights gaps in knowledge about the steps and epistatic relationships of enzymes necessary for enhancer activation and cognate gene transcription.
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