Pathway Human Homo sapiens

Formation of WDR5-containing histone-modifying complexes

R-HSA-9772755 in Reactome release 97: under Epigenetic regulation by WDR5-containing histone modifying complexes, with 42 genes placed in it by the mapping files and 0 child pathways 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-9772755 (mouse), R-RNO-9772755 (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-9772755.2
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2023-03-29
Events inside: 30, counted from the record

WDR5 is a component of six mammalian histone methyltransferase KMT2 complexes: Mixed Lineage Leukemia (MLL) 1-4, SET1A, and SET1B. All KMT2 complexes consist of a histone methyltransferase (KMT2A, KMT2B, KMT2C, KMT2D, SETD1A, or SETD1B, respectively) and the WRAD subcomplex composed of WDR5, RBBP5, ASH2L, and DPY30. The WRAD complex regulates the enzymatic activity of histone methyltransferases and enables their recruitment to chromatin. Additional transcription cofactors associate with each KMT2 histone methyltransferase complex, enabling their functional diversification. For a detailed overview, please refer to Cho et al. 2007, Song and Kingston 2008, Takahashi et al. 2011, Couture and Skiniotis 2013, van Nuland et al. 2013, Klonou et al. 2021.

The KMT2 complexes are evolutionarily conserved. While a single SET1/COMPASS complex is present in yeast, three distinct complexes are present in Drosophila: trithorax (Trx), trithorax-related (Trr), and Set1. In mammals, due to gene duplication, two Trx-like complexes (one with KMT2A and another with KMT2B as the catalytic subunit), as well as two Trr-like complexes (one with KMT2C and another with KMT2D as the catalytic subunit), and two Set1-like complexes (one with SETD1A and another with SETD1B as the catalytic subunit) are formed. For review, please refer to Rao and Dou 2015.

All KMT2 complexes methylate lysine K5 of histone H3 (K4 in mature histone H3 peptides, as the initiator methionine is removed), which is associated with transcriptional activation. Different KMT2 complexes preferentially monomethylate, dimethylate, or trimethylate H3K4, depending on the presence of accessory subunits, transcriptional co-factors, and posttranslational modifications. The catalytic activity of KMT2 complexes may differ between endogenous complexes and complexes reconstituted in vitro by mammalian proteins expressed and produced in bacterial or insect cells. The KMT2A and KMT2B complexes preferentially methylate H3K4 at a limited number of target gene promoters, while KMT2C and KMT2D complexes preferentially methylate H3K4 at a limited number of target gene enhancers. SETD1A and SETD1B complexes are responsible for the bulk of cellular H3K4 methylation and show less target specificity. For overview, please refer to Patel et al. 2009, Wang et al. 2009, Rao and Dou 2015.

In both Drosophila and vertebrates, KMT2 complexes control the expression of evolutionarily conserved Hox genes which serve as master regulators of embryonic patterning (reviewed in Soshnikova and Duboule 2009).

Germline mutations in human KMT2 complexes are the underlying cause of several chromatinopathies. Germline loss-of-function (LOF) mutations in KMT2A cause Weideman-Steiner syndrome, a rare autosomal-dominant disorder characterized by intellectual disability, developmental delay, pre- and post-natal growth delay, hypertrichosis, short stature, hypotonia, distinctive facial features, skeletal abnormalities, feeding problems and behavioral difficulties (reviewed in Castiglioni et al. 2022). Germline LOF mutations in KMT2B cause dystonia-28 (DYT28) and intellectual developmental, autosomal dominant disorder-68 (MRD68). DYT28 is an autosomal dominant neurologic disorder characterized by onset of progressive dystonia in the first decade of life (reviewed in Zech et al. 2019), while MRD68 is an autosomal dominant disorder characterized by developmental delay/intellectual disability, microcephaly, poor growth, feeding difficulties, and dysmorphic features (Cif et al. 2020). Germline LOF mutations in KMT2C cause Kleefstra syndrome-2 (KLEFS2), an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, variable intellectual disability, and mild dysmorphic features (reviewed in Lavery et al. 2020). Germline LOF mutations in KMT2D cause Kabuki syndrome 1, a congenital mental retardation syndrome with postnatal dwarfism, a facial dysmorphism and skeletal abnormalities (reviewed in Lavery et al. 2020). Germline LOF mutations in SETD1A cause early-onset epilepsy with or without developmental delay (EPEDD), an autosomal dominant neurologic disorder (Yu et al. 2019), and neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID) (Kummeling et al. 2021). Germline LOF mutations in SETD1B cause intellectual developmental disorder with seizures and language delay (IDDSELD) (Roston et al. 2021).

Somatic mutations in KMT2 genes contribute to cancer development. They were first discovered in Mixed Lineage Leukemia (MLL), characterized by chromosomal translocations that involve the KMT2A gene locus on chromosome 11 (chromosomal band 11q23) and result in the expression of fusion proteins with oncogenic properties. Besides gene fusions, other types of KMT2A mutations are also present in blood cancers (most frequently in high-grade B-cell lymphoma, T-cell lymphoblastic leukemia, and acute myeloid leukemia) and solid tumors (most often reported in lung adenocarcinoma, colon adenocarcinoma, and bladder urothelial carcinoma). Somatic cancer mutations in other KMT2 genes (KMT2B, KMT2C, KMT2D, SETD1A and SETD1B) are less characterized but most frequently affect the catalytic SET domain and show different distributions between different cancer types. For review, please refer to Rao and Dou 2015, Castiglioni et al. 2022. Several anti-cancer therapeutics are being developed that affect the association of KMT2 enzymes with components of the WRAD complex, in particular WDR5 (reviewed in Vedadi et al. 2017; Siladi et al. 2022).

WDR5 is also a component of three histone acetyltransferase complexes, GCN5-ATAC, PCAF-ATAC, and MOF/KAT8-NSL. The role of WDR5 in epigenetic regulation of gene expression through histone acetylation is under investigation (reviewed in Guarnaccia and Tansey 2018).

The function of WDR5-containing histone modifying complexes is currently depicted in the following Reactome pathways: "Transcriptional regulation of granulopoiesis" (MLL1 complex), "Transcriptional regulation by RUNX1" (MLL1 complex), "Activation of anterior HOX genes in hindbrain development during early embryogenesis" (MLL3 complex and MLL4 complex), "TCF dependent signaling in response to WNT" (MLL4 complex), and "Chromatin organization" (MLL1 complex, MLL2 complex, MLL3 complex, MLL4 complex, SET1A complex, SET1B complex, GCN5-ATAC complex, PCAF-ATAC complex, and MOF/KAT8-NSL complex). Please note that there is an inconsistency in naming of MLL2 and MLL4 complexes in the literature and in Reactome pathways, as MLL2 and MLL4 have been used as synonyms for both KMT2B and KMT2D, depending on whether the numbering of MLLs referred to order of cloning or whether it referred to similarity to founding MLL1 (MLL, KMT2A) enzyme. The current UniProt standard is for MLL2 to be used as the preferred synonym of KMT2B, and for MLL4 to be used as the preferred synonym of KMT2D.

Literature Reactome attaches

Assembling a COMPASSEpigenetics, 2013, vol. 8, p. 349-54PubMed 23470558
Structural analysis of the core COMPASS family of histone H3K4 methylases from yeast to humanProc Natl Acad Sci U S A, 2011, vol. 108, p. 20526-31PubMed 22158900
WDR5 interacts with mixed lineage leukemia (MLL) protein via the histone H3-binding pocketJ Biol Chem, 2008, vol. 283, p. 35258-64PubMed 18840606
Structure, Activity and Function of the MLL2 (KMT2B) Protein Lysine MethyltransferaseLife (Basel), 2021, vol. 11PubMed 34440566
Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexesMol Cell Biol, 2013, vol. 33, p. 2067-77PubMed 23508102
<i>KMT2A</i>: Umbrella Gene for Multiple DiseasesGenes (Basel), 2022, vol. 13PubMed 35328068
KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulationBrain, 2020, vol. 143, p. 3242-3261

Reactome's record lists 14 orthologous events, R-RNO-9772755 (Rattus norvegicus), R-MMU-9772755 (Mus musculus) among the species this site serves, and 12 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-01 ET · Reactome pathway browser"Formation of WDR5-containing histone-modifying complexes". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9772755 with StableID: R-HSA-9772755.2 (accessed 2026-10-01 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 42 genes in this human pathway; showing 1 to 42, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneAKAP8L	AuthorityHGNC:29857	Mapping file id26993 NCBI file	EvidenceTAS
GeneASH2L	AuthorityHGNC:744	Mapping file id9070 NCBI file	EvidenceTAS
GeneBOD1	AuthorityHGNC:25114	Mapping file id91272 NCBI file	EvidenceTAS
GeneBOD1L1	AuthorityHGNC:31792	Mapping file id259282 NCBI file	EvidenceTAS
GeneCXXC1	AuthorityHGNC:24343	Mapping file id30827 NCBI file	EvidenceTAS
GeneDPY30	AuthorityHGNC:24590	Mapping file id84661 NCBI file	EvidenceTAS
GeneDR1	AuthorityHGNC:3017	Mapping file id1810 NCBI file	EvidenceTAS
GeneHCFC1	AuthorityHGNC:4839	Mapping file id3054 NCBI file	EvidenceTAS
GeneHCFC2	AuthorityHGNC:24972	Mapping file id29915 NCBI file	EvidenceTAS
GeneKANSL1	AuthorityHGNC:24565	Mapping file id284058 NCBI file	EvidenceTAS
GeneKANSL2	AuthorityHGNC:26024	Mapping file id54934 NCBI file	EvidenceTAS
GeneKANSL3	AuthorityHGNC:25473	Mapping file id55683 NCBI file	EvidenceTAS
GeneKAT14	AuthorityHGNC:15904	Mapping file id57325 NCBI file	EvidenceTAS
GeneKAT2A	AuthorityHGNC:4201	Mapping file id2648 NCBI file	EvidenceTAS
GeneKAT2B	AuthorityHGNC:8638	Mapping file id8850 NCBI file	EvidenceTAS
GeneKAT8	AuthorityHGNC:17933	Mapping file id84148 NCBI file	EvidenceTAS
GeneKDM6A	AuthorityHGNC:12637	Mapping file id7403 NCBI file	EvidenceTAS
GeneKMT2A	AuthorityHGNC:7132	Mapping file id4297 NCBI file	EvidenceTAS
GeneKMT2B	AuthorityHGNC:15840	Mapping file id9757 NCBI file	EvidenceIEA, TAS
GeneKMT2C	AuthorityHGNC:13726	Mapping file id58508 NCBI file	EvidenceTAS
GeneKMT2D	AuthorityHGNC:7133	Mapping file id8085 NCBI file	EvidenceTAS
GeneMBIP	AuthorityHGNC:20427	Mapping file id51562 NCBI file	EvidenceTAS
GeneMCRS1	AuthorityHGNC:6960	Mapping file id10445 NCBI file	EvidenceTAS
GeneMEN1	AuthorityHGNC:7010	Mapping file id4221 NCBI file	EvidenceTAS
GeneNCOA6	AuthorityHGNC:15936	Mapping file id23054 NCBI file	EvidenceTAS
GeneOGT	AuthorityHGNC:8127	Mapping file id8473 NCBI file	EvidenceTAS
GenePAGR1	AuthorityHGNC:28707	Mapping file id79447 NCBI file	EvidenceTAS
GenePAXIP1	AuthorityHGNC:8624	Mapping file id22976 NCBI file	EvidenceTAS
GenePHF20	AuthorityHGNC:16098	Mapping file id51230 NCBI file	EvidenceTAS
GenePHF20L1	AuthorityHGNC:24280	Mapping file id51105 NCBI file	EvidenceTAS
GenePSIP1	AuthorityHGNC:9527	Mapping file id11168 NCBI file	EvidenceTAS
GeneRBBP5	AuthorityHGNC:9888	Mapping file id5929 NCBI file	EvidenceTAS
GeneSETD1A	AuthorityHGNC:29010	Mapping file id9739 NCBI file	EvidenceTAS
GeneSETD1B	AuthorityHGNC:29187	Mapping file id23067 NCBI file	EvidenceTAS
GeneSGF29	AuthorityHGNC:25156	Mapping file id112869 NCBI file	EvidenceTAS
GeneTADA2A	AuthorityHGNC:11531	Mapping file id6871 NCBI file	EvidenceTAS
GeneTADA3	AuthorityHGNC:19422	Mapping file id10474 NCBI file	EvidenceTAS
GeneTASP1	AuthorityHGNC:15859	Mapping file id55617 NCBI file	EvidenceIEA, TAS
GeneWDR5	AuthorityHGNC:12757	Mapping file id11091 NCBI file	EvidenceTAS
GeneWDR82	AuthorityHGNC:28826	Mapping file id80335 NCBI file	EvidenceTAS
GeneYEATS2	AuthorityHGNC:25489	Mapping file id55689 NCBI file	EvidenceTAS
GeneZZZ3	AuthorityHGNC:24523	Mapping file id26009 NCBI file	EvidenceTAS

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

None: no pathway of this release's list names this one as a parent.

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.