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Cited by 522Genomics and Chromatin DynamicsEpigenetics and DNA MethylationChromatin Remodeling and Cancer

H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation

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Lee, Ji-Eun, Wang, Chaochen, Xu, Shiliyang, Cho, Young-Wook, Wang, Lifeng, Feng, Xuesong, Baldridge, Anne, Sartorelli, Vittorio +3 more·2013·eLife
DOI 10.7554/elife.01503PMC PMC3869375
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Abstract

Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for H3K4me1/2 on enhancers remain elusive. Furthermore, how these enzymes function on enhancers to regulate cell-type-specific gene expression is unclear. In this study, we identify MLL4 (KMT2D) as a major mammalian H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C). Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of Mll4 markedly decreases H3K4me1/2, H3K27ac, Mediator and Polymerase II levels on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Together, these findings identify MLL4 as a major mammalian H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation.

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  • Loss of function mutations in MLL4 reduce global H3K4me1 levels, cause abnormal gene expression, and lead to developmental defects or cancer.

    “Loss of function mutations in MLL4 reduce global H3K4me1 levels, cause abnormal gene expression, and lead to developmental defects or cancer37.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [37]

    The Results report global H3K4me1 decreases after Mll4 deletion in Mll3-knockout cells and reduced expression of enhancer-associated genes after Mll4 deletion. The Discussion links MLL4 loss-of-function mutations to developmental diseases and cancers, but says the proposed mechanism “may contribute” to their pathogenesis; it does not establish that those mutations cause cancer. The global H3K4me1 result also comes from cells lacking both MLL3 and MLL4, not MLL4 alone. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • MLL4 exists in a multi-protein complex containing core components WDR5, ASH2L, RBBP5 and DPY30 and other complex-specific proteins such as PAGR1, KDM6A, NCOA6 and PAXIP1.

    “MLL4 exists in a multi-protein complex containing the core components WDR5, ASH2L, RBBP5 and DPY3038,39 and other complex-specific proteins, such as PAGR1 (previously known as PA1), KDM6A (UTX), NCOA6 and PAXIP1 (PTIP)37,40.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [37]

    The Results (Figure 4F; page unavailable) identify UTX, PTIP and PA1 as MLL3/MLL4 complex components, supporting the cited portion of the sentence for KDM6A, PAXIP1 and PAGR1. Our copy does not identify NCOA6 as a component. The citation to this paper is attached to the complex-specific proteins, not the preceding list of core components. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • MLL4 co-localizes with lineage-specific TFs such as C/EBPβ, PPARγ, EBF1 and GR at enhancers to ensure increased expression of cell-type-specific genes that establish lineage maturity.

    “MLL4 has also been shown to co-localize with lineage-specific TFs such as C/EBPβ, PPARγ, EBF1 and GR at enhancers to ensure increased expression of cell-type-specific genes that establish lineage maturity37.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [37]

    The Results sections on genomic co-localization and active enhancers show MLL4 co-localizing with C/EBPβ and PPARγ at adipogenic enhancers. The Results section on cell-type-specific gene expression reports that Mll4 deletion reduces expression of genes associated with MLL4-positive enhancers. For EBF1 and GR, however, the paper reports enriched binding motifs at MLL4 sites, not measured co-localization; it also does not establish that the affected genes confer lineage maturity. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • MLL3 and MLL4 catalyze H3K4 monomethylation and are recruited to target enhancers by TFs and pioneer factors.

    “MLL3 and MLL4 catalyze H3K4 monomethylation and are recruited to target enhancers by TFs and pioneer factors37,38,59.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [37]

    The Introduction identifies MLL4 as a major H3K4 mono- and di-methyltransferase that is partially redundant with MLL3. The Results and Discussion say that lineage-determining TFs, including the pioneer TF C/EBPβ, recruit MLL4 to enhancers. Our copy does not establish that MLL3 is likewise recruited by those factors. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • 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 [37]

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Cited by

Sorted by citations

Authors
Lee, J.-E., Wang, C., Xu, S., Cho, Y.-W., Wang, L., Feng, X., Baldridge, A., Sartorelli, V., Zhuang, L., Peng, W., & Ge, K.
Affiliations
  • National Institutes of Health (US)
  • George Washington University (US)
Corresponding author
  • Peng, Weiqun
  • Ge, Kai
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2013-12-24
Volume
2
Pages
e01503-e01503
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.01503
PMC
PMC3869375
OpenAlex
W2130560229
Cited by
522
References
11
Citations by year
2026: 38 · 2025: 45 · 2024: 48 · 2023: 42 · 2022: 33 · 2021: 49 · 2020: 61 · 2019: 45 · 2018: 39 · 2017: 33 · 2016: 40 · 2015: 28 · 2014: 21
FWCI
13.30
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • arXiv (Cornell University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • arXiv (Cornell University) (public-domain)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (1ZIADK075003)
  • National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health (1ZIAAR041126)
  • National Institute of Diabetes and Digestive and Kidney Diseases (1ZIADK075003)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (1ZIAAR041126)
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
KMT2D, H3K4 methylation, enhancer activation, enhancers, cell differentiation, adipogenesis, myogenesis, MLL3, KMT2C, H3K27ac, Mediator complex, RNA polymerase II, lineage-specific transcription factors, cell type-specific gene expression
MeSH terms
Animals, Binding Sites, DNA Polymerase II, DNA-Binding Proteins, Enhancer Elements, Genetic, Histones, Humans, Methylation, Promoter Regions, Genetic, Histone-Lysine N-Methyltransferase, Time Factors, Transcription Factors, Transfection, Adipocytes, Mice, Knockout, Gene Expression Regulation, Developmental, Cell Lineage, Computational Biology, Genomics, Muscle Development, Muscle Cells, 3T3-L1 Cells, Adipogenesis, Mice, Mediator Complex

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