Formation of WDR5-containing histone-modifying complexes

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. 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, and neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID). Germline LOF mutations in SETD1B cause intellectual developmental disorder with seizures and language delay (IDDSELD).

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.