The MLL3/MLL4 Branches of the COMPASS Family Function as Major Histone H3K4 Monomethylases at Enhancers
Open accessAbstract
Histone H3 lysine 4 (H3K4) can be mono-, di-, and trimethylated by members of the COMPASS (complex of proteins associated with Set1) family from Saccharomyces cerevisiae to humans, and these modifications can be found at distinct regions of the genome. Monomethylation of histone H3K4 (H3K4me1) is relatively more enriched at metazoan enhancer regions compared to trimethylated histone H3K4 (H3K4me3), which is enriched at transcription start sites in all eukaryotes. Our recent studies of Drosophila melanogaster demonstrated that the Trithorax-related (Trr) branch of the COMPASS family regulates enhancer activity and is responsible for the implementation of H3K4me1 at these regions. There are six COMPASS family members in mammals, two of which, MLL3 (GeneID 58508) and MLL4 (GeneID 8085), are most closely related to Drosophila Trr. Here, we use chromatin immunoprecipitation-sequencing (ChIP-seq) of this class of COMPASS family members in both human HCT116 cells and mouse embryonic stem cells and find that MLL4 is preferentially found at enhancer regions. MLL3 and MLL4 are frequently mutated in cancer, and indeed, the widely used HCT116 cancer cell line contains inactivating mutations in the MLL3 gene. Using HCT116 cells in which MLL4 has also been knocked out, we demonstrate that MLL3 and MLL4 are major regulators of H3K4me1 in these cells, with the greatest loss of monomethylation at enhancer regions. Moreover, we find a redundant role between Mll3 (GeneID 231051) and Mll4 (GeneI…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [36]
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 [36]
Cites
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · see citing works
High-Resolution Profiling of Histone Methylations in the Human Genome
Barski, A., Cuddapah, S., Cui, K., Roh, T.-Y., Schones, D. E., Wang, Z., Wei, G., Chepelev, I., & Zhao, K. (2007) · Cell · doi:10.1016/j.cell.2007.05.009 · Cited by 6,845 · see citing works
Heintzman, N. D., Stuart, R. K., Hon, G., Fu, Y., Ching, C. W., Hawkins, R. D., Barrera, L. O., Van Calcar, S., Qu, C., Ching, K. A., et al. (2007) · Nature Genetics · doi:10.1038/ng1966 · Cited by 3,398 · cited 4× · see citing works
“Histone H3K4me1 was the first histone modification found to have a global association/correlation with enhancer regions (3); additional modifications such as H3K27ac and H3K27me3 were subsequently shown to associate with only a subset of enhancers (4, 5, 7).”
BackgroundInfluentialA unique chromatin signature uncovers early developmental enhancers in humans
Rada-Iglesias, A., Bajpai, R., Swigut, T., Brugmann, S. A., Flynn, R. A., & Wysocka, J. (2011) · Nature · doi:10.1038/nature09692 · Cited by 2,233 · see citing works
Genomic views of distant-acting enhancers
Visel, A., Rubin, E. M., & Pennacchio, L. A. (2009) · Nature · doi:10.1038/nature08451 · Cited by 610 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Roles and regulation of histone methylation in animal development
Jambhekar, A., Dhall, A., & Shi, Y. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0151-1 · Cited by 556 · see citing works
Born to run: control of transcription elongation by RNA polymerase II
Chen, F. X., Smith, E. R., & Shilatifard, A. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0010-5 · Cited by 447 · see citing works
Self-citationDorighi, 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
Andricovich, J., Perkail, S., Kai, Y., Casasanta, N., Peng, W., & Tzatsos, A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.02.003 · Cited by 320 · see citing works
Epigenetic regulation of female puberty
Lomniczi, A., Wright, H., & Ojeda, S. R. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.08.003 · Cited by 136 · see citing works
H3K4me1 Distribution Predicts Transcription State and Poising at Promoters
Bae, S., & Lesch, B. J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00289 · Cited by 120 · see citing works
Kang, Y., Kim, Y. W., Kang, J., & Kim, A. (2021) · The FASEB Journal · doi:10.1096/fj.202100488r · Cited by 93 · see citing works
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
Decoding the role of TET family dioxygenases in lineage specification
Wu, X., Li, G., & Xie, R. (2018) · Epigenetics & Chromatin · doi:10.1186/s13072-018-0228-7 · Cited by 43 · 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
O-GlcNAcylation of FOXK1 orchestrates the E2F pathway and promotes oncogenesis
Masclef, L., Ahmed, O., Iannantuono, N., Gagnon, J., Gushul-Leclaire, M., Boulay, K., Estavoyer, B., Echbicheb, M., Poy, M., Ali Boubacar, K., et al. (2024) · doi:10.1101/2024.03.01.582838 · Cited by 6 · see citing works
Choppavarapu, L., Nosirov, B., Kahn, M., & Jin, V. X. (2026) · Cancers · doi:10.3390/cancers18213416
- Authors
- Hu, D., Gao, X., Morgan, M. A., Herz, H.-M., Smith, E. R., & Shilatifard, A.
- Affiliations
- Stowers Institute for Medical Research (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2013-12-01
- Volume
- 33
- Issue
- 23
- Pages
- 4745-4754
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3838007
- OpenAlex
- W2170748964
- Cited by
- 439
- References
- 5
- Citations by year
- 2026: 28 · 2025: 39 · 2024: 27 · 2023: 41 · 2022: 32 · 2021: 39 · 2020: 42 · 2019: 36 · 2018: 33 · 2017: 35 · 2016: 31 · 2015: 32 · 2014: 23 · 2013: 1
- FWCI
- 13.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- 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, H3K4me1, enhancers, enhancer activity, HCT116 cells, mouse embryonic fibroblasts, gene expression regulation
- MeSH terms
- Animals, DNA-Binding Proteins, Enhancer Elements, Genetic, Histones, Humans, Methylation, Neoplasms, Histone-Lysine N-Methyltransferase, Protein Processing, Post-Translational, Gene Expression, Protein Transport, Epigenesis, Genetic, HCT116 Cells, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
