Pathway Human Homo sapiens

Epigenetic regulation of gene expression by MLL3 and MLL4 complexes

R-HSA-9818564 in Reactome release 97: under Epigenetic regulation by WDR5-containing histone modifying complexes, with 134 genes placed in it by the mapping files and 1 child pathway in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-9818564 (mouse), R-RNO-9818564 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-9818564.3
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2024-09-11
Events inside: 4, counted from the record

The KMT2C (MLL3) complex, together with the related KMT2D (MLL4) complex, is most similar to Drosophila Trr (Trithorax-related) and mediates histone H3 lysine-4 (H3K4 - lysine 5 in nascent histone H3) monomethylation, with the establishment of the H3K4me1 epigenetic marks, at transcription enhancers throughout the human genome (For review, please refer to Hu et al. 2013, Piunti and Shilatifard 2016, Klonou et al. 2021).

The MLL3 and MLL4 complexes monomethylate H3K4 at transcription enhancers throughout the human genome, with estimates ranging from approximately 12,000 to over 20,000 sites, depending on the cell type and developmental stage. Full activation of gene expression through MLL3 and MLL4 complex target enhancers appears to require simultaneous monomethylation of H3K4 by MLL3 and/or MLL4 complexes, and acetylation of H3K27 by the histone acetyltransferase p300/CBP, recruited to enhancers through direct interactions with the MLL3 and MLL4 complexes (Wang et al. 2017). KDM6A (also known as UTX), a lysine demethylase that acts as an accessory subunit of MLL3 and MLL4 complexes, facilitates H3K27 acetylation by removing inhibitory methyl groups from H3K27, deposited by the Polycomb repressor PRC2 complex (reviewed in Fagan and Dingwall 2019).

KMT2C (also known as MLL3), the catalytic subunit of the MLL3 complex, contains two closely related plant homeodomain (PHD) zinc finger clusters, with 6-7 zinc fingers, in the N-terminal region, and a single PHD zinc finger near the C-terminus, which are involved in protein-protein interactions. The HMG domain in KMT2C enables DNA binding, while the SET domain provides catalytic activity. KMT2C possesses multiple nuclear receptor (NR) interaction motifs (LLXXL or LXXLL), which are important for recruitment of the MLL3 complex to NR-regulated enhancers (reviewed in Fagan and Dingwall 2019).

While H3K4 monomethylation by MLL3 and MLL4 complexes may not be essential for expression of developmental genes, it is likely important for fine tuning of transcription levels and timing, both during normal development and in cancer. Although a broad dispersion of cancer mutations in the coding regions of the KMT2C and KMT2D genes, as well as the presence of many truncating mutations, imply a tumor suppressor role, activating mutations in the SET domains have also been reported, suggesting that a tumor suppressive vs. oncogenic role is context-dependent (reviewed in Fagan and Dingwall 2019).

KMT2C is frequently mutated in cancer. KMT2C may be important for driving hormone-stimulated proliferation of breast cancer cells that are ESR1-positive and ERBB2-negative. In mice, simultaneous overexpression of Pik3ca and inactivation of the Kmt2c blocks differentiation of the mammary gland and leads to increased stem cell self-renewal through HIF pathway activation (reviewed in Fagan and Dingwall 2019).

Non-small cell lung cancer (NSCLC) is characterized by frequent co-occurrence of mutations in KMT2C and KMT2D (also known as MLL4, the catalytic subunit of the MLL4 complex) (reviewed in Fagan and Dingwall 2019).

DNA damage-induced transcription of TP53 target genes requires both KMT2C and KMT2D. KMT2C is also implicated in TP53-dependent DNA double strand break repair in a transcription-independent manner. KMT2C and KMT2D contribute to maintenance of epithelial cell states by negatively regulating the epithelial-to-mesenchymal transition. KMT2C mutations in lung and breast cancer are frequently found in the first PHD that is involved in the interaction with the BAP1 histone deubiquitinating complex, linked to Polycomb repressor complex-dependent gene silencing (reviewed in Fagan and Dingwall 2019).

Heterozygous germline LOF mutations in KTM2C are associated with Kleefstra syndrome-2 and autism spectrum disorder (reviewed in Fagan and Dingwall 2019).

In mouse, Kmt2c and Kmt2d are implicated in enhancer priming and de novo enhancer activation during embryonic development. This function is not essential for the maintenance of cell identity and self-renewal of embryonic stem cells (ESCs) and somatic cells but is necessary for ESC reprogramming during differentiation and for production of induced pluripotent stem cells (iPSCs) (reviewed in Fagan and Dingwall 2019).

Knockout of KMT2D, the catalytic subunit of the MLL4 complex, in human colon carcinoma cell line HCT116, which already harbors inactivating mutations in both alleles of KMT2C (the catalytic subunit of the MLL3 complex), leads to significant global reduction of H3K4 monomethylation (Hu et al. 2013). Knockout studies of KMT2C and KMT2D in HCT116 cells and mouse embryonic fibroblasts (MEFs) implicate at least partially redundant roles of MLL3 and MLL4 complexes in H3K4 monomethylation (Hu et al. 2013). Genome-wide ChIP-seq analysis in both HCT116 cells and MEFs showed that ~80% of the MLL4 peaks are enriched at intergenic and intragenic regions, while only ~20% of the peaks map to transcription start sites (TSS) (Hu et al. 2013). MLL4 binding sites at SAE1 and AP3B1 gene loci in HCT116 cells, and at Nanog and Lefty1 loci in MEFs, are co-occupied by enhancer region markers H3K4me1, EP300, and acetylated H3K27 (Hu et al. 2013). Many of the genes associated with MLL3/MLL4-bound enhancers in HCT116 cells are implicated in intracellular signaling, while genes associated with MLL3/MLL4-independent enhancers tend to be implicated in regulation of gene expression (Hu et al. 2013).

HOXA9, encoded by a target gene of KMT2A (MLL1) and KMT2B (MLL2) complexes, may function as a pioneer factor at de novo enhancers in acute myeloid leukemia (AML) and recruit CEBPA and the MLL3 and MLL4 complexes to enhancers of leukemogenesis-promoting genes (Sun et al. 2018).

KMT2D is frequently mutated in cancer (reviewed in Dhar and Lee 2021) and is one of the most frequently mutated genes in non-Hodgkin lymphoma, such as follicular lymphoma and diffuse large B cell lymphoma, where loss-of-function (LOF) of KMT2D appears to be an early event that cooperates with the over-expression of the BCL2 oncogene. Knockout of Kmt2d in mouse B cell progenitors impairs their differentiation and promotes lymphoma development. KMT2D LOF in lymphoma is associated with reduced H3K4me1 mark at enhancers of multiple tumor suppressor genes (reviewed in Fagan and Dingwall 2019).

KMT2D chromatin enrichment sites significantly overlap with TP53 binding sites. Aberrant transcription associated with TP53 mutations in colon carcinoma is dependent on KMT2D-mediated H3K4 monomethylation. KMT2D can be inactivated through phosphorylation by SGK1, a PI3K effector kinase closely related to AKT1. SGK1 is the estrogen-inducible kinase, whose transcription is collaboratively activated by ESR1 and KMT2D. SGK1-mediated phosphorylation on KMT2D on serine S1331 near the second PHD results in downregulation of H3K4 monomethylation at ESR1-target genes, thus constituting a negative feedback loop (reviewed in Fagan and Dingwall 2019).

Heterozygous germline LOF mutations in KMT2D are associated with Kabuki syndrome. Kabuki syndrome patients have a modestly increased predisposition to cancer, in particular lymphoma, Wilms tumor, hepatoblastoma, synovial sarcoma and neuroblastoma. Mice with brain-specific knockout of Kmt2d (Mll4) develop medulloblastoma that shows hyperactivation of Ras and Notch signaling (reviewed in Fagan and Dingwall 2019).

Based on mouse studies, MLL3 and MLL4 complexes play an important role in adipogenesis and myogenesis. Kmt2c KO mice die around birth with no obvious morphological abnormalities in embryonic development, while Kmt2d KO mice show early embryonic lethality around E9.5 (Lee et al. 2013). Pups with Kmt2d KO in precursors of brown preadipocytes and skeletal myocytes are obtained at the expected Mendelian ratio but display marked reduction in back muscles and die immediately after birth due to breathing malfunction, also showing a decrease in brown adipose tissue mass (Lee et al. 2013). In cultured mouse brown preadipocytes, KO of Kmt2d leads to a moderate differentiation defect along with a transient up-regulation of Kmt2c expression, whereas KO of Kmt2c has no effect on adipogenesis, suggesting a more prominent role of KMT2D in development and a partial compensation of KMT2D loss by KMT2C (Lee et al. 2013). KO of Kmt2d 3T3-L1 mouse white preadipocytes inhibits adipogenesis, and Kmt2c and Kmt2d are also required for adipogenesis in mouse embryonic fibroblasts (Lee et al. 2013). By ChIP-seq, the average length of Kmt2d binding regions is between 350 and 400 bp, and the binding regions change dramatically from the preadipocytes stage to the onset of adipogenesis, but are then Kmt2d-binding regions were largely non-overlapping between brown adipocytes and skeletal myocytes (Lee et al. 2013).

Literature Reactome attaches

Histone H3K27 trimethylation inhibits H3 binding and function of SET1-like H3K4 methyltransferase complexesMol Cell Biol, 2013, vol. 33, p. 4936-46PubMed 24126056
The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancersMol Cell Biol, 2013, vol. 33, p. 4745-54PubMed 24081332
HOXA9 Reprograms the Enhancer Landscape to Promote LeukemogenesisCancer Cell, 2018, vol. 34, p. 643-658.e5PubMed 30270123
COMPASS Ascending: Emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancerCancer Lett, 2019, vol. 458, p. 56-65PubMed 31128216
Cancer-epigenetic function of the histone methyltransferase KMT2D and therapeutic opportunities for the treatment of KMT2D-deficient tumorsOncotarget, 2021, vol. 12, p. 1296-1308PubMed 34194626
Structure, Activity and Function of the MLL2 (KMT2B) Protein Lysine MethyltransferaseLife (Basel), 2021, vol. 11PubMed 34440566
Epigenetic balance of gene expression by Polycomb and COMPASS families

Reactome's record lists 9 orthologous events, R-RNO-9818564 (Rattus norvegicus), R-MMU-9818564 (Mus musculus) among the species this site serves, and 7 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-30 ET · Reactome pathway browser"Epigenetic regulation of gene expression by MLL3 and MLL4 complexes". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9818564 with StableID: R-HSA-9818564.3 (accessed 2026-09-30 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 134 genes in this human pathway; showing 101 to 134, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 2 of 2
Gene	Authority id	Mapping file id	Evidence codes
GeneMED31	AuthorityHGNC:24260	Mapping file id51003 NCBI file	EvidenceIEA, TAS
GeneMED4	AuthorityHGNC:17903	Mapping file id29079 NCBI file	EvidenceIEA, TAS
GeneMED6	AuthorityHGNC:19970	Mapping file id10001 NCBI file	EvidenceIEA, TAS
GeneMED7	AuthorityHGNC:2378	Mapping file id9443 NCBI file	EvidenceIEA, TAS
GeneMGLL	AuthorityHGNC:17038	Mapping file id11343 NCBI file	EvidenceIEA
GeneNCOA1	AuthorityHGNC:7668	Mapping file id8648 NCBI file	EvidenceIEA, TAS
GeneNCOA2	AuthorityHGNC:7669	Mapping file id10499 NCBI file	EvidenceIEA, TAS
GeneNCOA3	AuthorityHGNC:7670	Mapping file id8202 NCBI file	EvidenceIEA, TAS
GeneNCOA6	AuthorityHGNC:15936	Mapping file id23054 NCBI file	EvidenceIEA, TAS
GeneNCOR1	AuthorityHGNC:7672	Mapping file id9611 NCBI file	EvidenceIEA, TAS
GeneNCOR2	AuthorityHGNC:7673	Mapping file id9612 NCBI file	EvidenceIEA, TAS
GeneNR5A2	AuthorityHGNC:7984	Mapping file id2494 NCBI file	EvidenceIEA
GenePAGR1	AuthorityHGNC:28707	Mapping file id79447 NCBI file	EvidenceIEA, TAS
GenePAXIP1	AuthorityHGNC:8624	Mapping file id22976 NCBI file	EvidenceIEA, TAS
GenePDK4	AuthorityHGNC:8812	Mapping file id5166 NCBI file	EvidenceIEA
GenePEX11A	AuthorityHGNC:8852	Mapping file id8800 NCBI file	EvidenceIEA
GenePHLDA1	AuthorityHGNC:8933	Mapping file id22822 NCBI file	EvidenceIEA
GenePLIN1	AuthorityHGNC:9076	Mapping file id5346 NCBI file	EvidenceIEA
GenePLIN2	AuthorityHGNC:248	Mapping file id123 NCBI file	EvidenceIEA
GenePLIN4	AuthorityHGNC:29393	Mapping file id729359 NCBI file	EvidenceIEA
GenePNPLA2	AuthorityHGNC:30802	Mapping file id57104 NCBI file	EvidenceIEA
GenePPARG	AuthorityHGNC:9236	Mapping file id5468 NCBI file	EvidenceIEA, TAS
GenePPARGC1A	AuthorityHGNC:9237	Mapping file id10891 NCBI file	EvidenceIEA, TAS
GenePPARGC1B	AuthorityHGNC:30022	Mapping file id133522 NCBI file	EvidenceIEA, TAS
GeneRB1	AuthorityHGNC:9884	Mapping file id5925 NCBI file	EvidenceTAS
GeneRBBP5	AuthorityHGNC:9888	Mapping file id5929 NCBI file	EvidenceIEA, TAS
GeneRXRA	AuthorityHGNC:10477	Mapping file id6256 NCBI file	EvidenceIEA, TAS
GeneSCD	AuthorityHGNC:10571	Mapping file id6319 NCBI file	EvidenceIEA
GeneSCD5	AuthorityHGNC:21088	Mapping file idENSG00000145284 Ensembl file	EvidenceIEA, TAS
GeneSIRT1	AuthorityHGNC:14929	Mapping file id23411 NCBI file	EvidenceTAS
GeneTBL1X	AuthorityHGNC:11585	Mapping file id6907 NCBI file	EvidenceIEA, TAS
GeneTBL1XR1	AuthorityHGNC:29529	Mapping file id79718 NCBI file	EvidenceIEA, TAS
GeneTHRSP	AuthorityHGNC:11800	Mapping file id7069 NCBI file	EvidenceIEA
GeneWDR5	AuthorityHGNC:12757	Mapping file id11091 NCBI file	EvidenceIEA, TAS

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Epigenetic regulation by WDR5-containing histone modifying complexesR-HSA-9917777166 genes

Children

Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexesR-HSA-9851695134 genes

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.