Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition
Open accessAbstract
Significance: Transcriptional enhancers control cell-identity gene expression and thus determine cell identity. Enhancers are primed by histone H3K4 mono-/di-methyltransferase MLL4 before they are activated by histone H3K27 acetyltransferase p300. Here, we show that MLL4 is dispensable for cell-identity maintenance but essential for cell fate transition using several model systems including embryonic stem cell (ESC) differentiation toward somatic cells and somatic cell reprogramming into ESC-like cells. Mechanistically, MLL4 is dispensable for maintaining p300 binding on active enhancers of cell-identity genes but is required for p300 binding on enhancers activated during cell fate transition. These results indicate that, although enhancer priming by MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating p300-mediated enhancer activation.
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Recent studies showed that the MLL4 complex recruits and activates p300 activity, involving UTX, at enhancers, resulting not only in methylation at H3K4 but also acetylation on H3K27 at target chromatin.
“recent studies showed that the MLL4 complex recruits and activates p300 activity, involving UTX, at enhancers, resulting not only in methylation at H3K4 but also acetylation on H3K27 at target chromatin41,61.”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [41]
The Significance section reports that MLL4 is required for p300 recruitment and H3K27ac deposition at de novo enhancers during embryonic stem-cell differentiation; the paper also identifies MLL4 as an H3K4 methyltransferase. Our copy does not show that UTX participates in this mechanism or that MLL4 activates p300's enzymatic activity, rather than enabling its recruitment. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWhile MLL4 is required for cell fate transition, not all enhancers are primed prior to differentiation and MLL4 is not required for the maintenance of cell identity.
“Interestingly, while MLL4 is required for cell fate transition, not all enhancers are primed prior to differentiation and MLL4 is not required for the maintenance of cell identity41.”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [41]
MLL4 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 [41]
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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. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.018 · Cited by 403 · see citing works
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The MLL3/4 H3K4 methyltransferase complex in establishing an active enhancer landscape
Wang, L.-H., Aberin, M. A. E., Wu, S., & Wang, S.-P. (2021) · Biochemical Society Transactions · doi:10.1042/bst20191164 · Cited by 53 · see citing works
HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements
Thakur, A., Park, K., Cullum, R., Fuglerud, B. M., Khoshnoodi, M., Drissler, S., Stephan, T. L., Lotto, J., Kim, D., Gonzalez, F. J., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-05835-0 · Cited by 10 · see citing works
- Authors
- Wang, C., Lee, J.-E., Lai, B., Macfarlan, T. S., Xu, S., Zhuang, L., Liu, C., Peng, W., & Ge, K.
- Affiliations
- National Institutes of Health (US)
- George Washington University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-10-03
- Volume
- 113
- Issue
- 42
- Pages
- 11871-11876
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5081576
- OpenAlex
- W2528171814
- Cited by
- 242
- References
- 7
- Citations by year
- 2026: 18 · 2025: 28 · 2024: 26 · 2023: 29 · 2022: 25 · 2021: 25 · 2020: 33 · 2019: 19 · 2018: 22 · 2017: 16 · 2016: 1
- FWCI
- 10.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (1ZIADK075003)
- 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 › Pluripotent Stem Cells Research
- Keywords
- KMT2D, H3K4 methylation, P300, H3K27 acetylation, enhancer activation, cell fate transitions, cell identity genes, mouse embryonic stem cells, induced pluripotent stem cells, cellular reprogramming, self-renewal, MLL3, histone methyltransferase
- MeSH terms
- Cell Self Renewal, Animals, Cell Differentiation, Cell Line, DNA-Binding Proteins, Enhancer Elements, Genetic, Fibroblasts, Gene Expression Regulation, Histones, Models, Biological, Promoter Regions, Genetic, Protein Binding, Histone-Lysine N-Methyltransferase, Biomarkers, E1A-Associated p300 Protein, Mice, Embryonic Stem Cells, Gene Knockout Techniques, Induced Pluripotent Stem Cells, Cellular Reprogramming
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