Formation of WDR5-containing histone-modifying complexes

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Homo sapiens
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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 et al. 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 References
PubMed ID Title Journal Year
19703992 Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II

Ge, K, Gogol, M, Wiedemann, LM, Seidel, C, Guo, H, Smith, ER, Alexander, T, Sanderson, BW, Lin, C, Wang, P, Wu, M, Shilatifard, A, Krumlauf, R

Mol. Cell. Biol. 2009
17500065 PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex

Ge, K, Guo, H, Hong, S, Hong, T, Yu, H, Copeland, TD, Kim, D, Dressler, GR, Guszczynski, T, Cho, YW, Kalkum, M

J. Biol. Chem. 2007
35115608 WIN site inhibition disrupts a subset of WDR5 function

Liu, Q, Florian, AC, Flaherty, DK, Thomas, LR, Weissmiller, AM, Creighton, JH, Matlock, BK, Lorey, SL, Tansey, WP, Fesik, SW, Wang, J, Siladi, AJ, Howard, GC

Sci Rep 2022
31197650 De Novo and Inherited SETD1A Variants in Early-onset Epilepsy

Yang, L, Wu, K, Qiu, Z, Chen, W, Li, W, Wang, R, Zhang, Y, Li, D, Li, J, Yu, X, Zhou, W

Neurosci Bull 2019
25998713 Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

Dou, Y, Rao, RC

Nat Rev Cancer 2015
32346159 Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

Man, CCO, Cho, MT, Pfundt, R, Hoffman, TL, Wheless, JW, Casey, AM, Steindl, K, Terhal, PA, van der Smagt, JJ, Schwaibold, EMC, Kummeling, J, Powell-Hamilton, NN, Genetti, CA, Agrawal, PB, McWalter, K, Koolen, DA, Sinnema, M, Rauch, A, Raun, N, Bodamer, O, Stremmelaar, DE, Bahr, A, Schubert, D, Zhou, D, Engleman, K, Thiffault, I, Simon, MEH, Kramer, JM, Tasic, V, Hoefele, J, Top, D, Kleefstra, T, Joset, P, Raas-Rothschild, A, Reijnders, MRF, Keller, E, Willemsen, MH, Riedhammer, KM, Gilissen, C, van Gassen, KLI, Schepens, M, Ruiterkamp-Versteeg, M, Higgs, MR

Mol Psychiatry 2021
31768667 Update on KMT2B-Related Dystonia

Zech, M, Winkelmann, J, Lam, DD

Curr Neurol Neurosci Rep 2019
33150406 KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation

Hamosh, A, Mondain, M, Krier, JB, Cyprien, F, Hallett, M, Mills, KA, Gregory, A, Coubes, C, Vasques, X, Hayflick, SJ, Dorison, N, Lee, H, Applegate, CD, Malhotra, S, Cif, L, Tchan, M, Hully, M, Mohammad, SS, Selim, L, Bhatia, KP, Roujeau, T, Dy-Hollins, ME, Barwick, KE, Zhen, D, Rogers, C, Farrelly, E, Pal, S, Abela, L, Fung, VSC, Lynch, T, Toro, C, de Gusmão, CM, Sharma, N, Fogel, BL, Study, DDD, Sa, M, Pavillard, F, Jeong, SY, Laurencin, C, Sanchis-Juan, A, Roubertie, A, Cambonie, G, Martinez-Agosto, JA, Kumar, KR, Milesi, C, Meyer, E, Mahant, N, Doja, A, Gorman, KM, Lesca, G, Fieg, EL, de Vries, BBA, Research Consortium, GERC, Soldatos, AG, Stewart, F, Bassetti, JA, Jansen, S, Steel, D, Trump, N, Graves, TD, Burglen, L, Baleine, J, Polo, G, Galosi, S, Chong, WK, Sahagian, M, Raymond, FL, Hasegawa, H, Lin, JP, Attaripour Isfahani, S, Rinne, T, Blanchet, C, Ostergaard, JR, Waugh, JL, Demailly, D, Krystal, S, d'Hardemare, V, Gahl, WA, Doummar, D, Forman, EB, Seng, EC, Fox, RG, Verma, IC, BioResource, NIHR, Allain, MW, Zaitoun, R, Stevenson, DA, Ngoh, A, Poulen, G, Coubes, P, Signer, R, King, MD, Selway, R, Network, UDN, Balint, B, Friedman, J, Baple, EL, Rankin, J, Pallais, JC, Dale, RC, Bastaraud, SC, Gonzalez, V, FitzPatrick, DR, Petersen, AK, Wilson, JL, Wong, DA, Morales-Briceno, H, Schaefer, E, Perrigault, PF, Fearon, C, Znaczko, A, François, LL, Rohena, L, Topf, M, Kurian, MA

Brain 2020
31924266 KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies

Lindsley, AW, Lavery, WJ, Barski, A, Wiley, S, Schorry, EK

Clin Epigenetics 2020
32546566 SETD1B-associated neurodevelopmental disorder

Farrer, M, Isidor, B, Demos, M, Jones, SJM, Evans, D, van Karnebeek, C, Study, CAUSES, Connolly, M, Roston, A, Gill, H, Mwenifumbo, J, McKinnon, M, Gibson, WT, An, J, Cogné, B, Study, EPGEN

J Med Genet 2021
35328068 KMT2A: Umbrella Gene for Multiple Diseases

Grazioli, P, Castiglioni, S, Bernardelli, C, Vignoli, A, Ancona, S, Colombo, EA, Ghelma, F, Di Fede, E, Lesma, E, Parodi, C, Massa, V, Borghi, E, Milani, D, Lettieri, A, Ottaviano, E, Gervasini, C

Genes (Basel) 2022
34440566 Structure, Activity and Function of the MLL2 (KMT2B) Protein Lysine Methyltransferase

Piperi, C, Chlamydas, S, Klonou, A

Life (Basel) 2021
28160335 Targeting human SET1/MLL family of proteins

Arrowsmith, CH, Vedadi, M, Eram, MS, Hajian, T, Barsyte-Lovejoy, D, Blazer, L

Protein Sci. 2017
19923920 Epigenetic regulation of vertebrate Hox genes: a dynamic equilibrium

Soshnikova, N, Duboule, D

Epigenetics 2009
22158900 Structural analysis of the core COMPASS family of histone H3K4 methylases from yeast to human

Skiniotis, G, Shilatifard, A, Takahashi, YH, Trievel, RC, Oleskie, AN, Westfield, GH

Proc Natl Acad Sci U S A 2011
29385767 Moonlighting with WDR5: A Cellular Multitasker

Tansey, WP, Guarnaccia, AD

J Clin Med 2018
23508102 Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes

Pallaki, P, Smits, AH, van Nuland, R, Jansen, PW, Timmers, HT, Vermeulen, M

Mol Cell Biol 2013
18840606 WDR5 interacts with mixed lineage leukemia (MLL) protein via the histone H3-binding pocket

Kingston, RE, Song, JJ

J Biol Chem 2008
19556245 On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex

Patel, A, Vought, VE, Cosgrove, MS, Dharmarajan, V

J. Biol. Chem. 2009
23470558 Assembling a COMPASS

Couture, JF, Skiniotis, G

Epigenetics 2013
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