KMT2A: Umbrella Gene for Multiple Diseases

Abstract

KMT2A (Lysine methyltransferase 2A) is a member of the epigenetic machinery, encoding a lysine methyltransferase responsible for the transcriptional activation through lysine 4 of histone 3 (H3K4) methylation. KMT2A has a crucial role in gene expression, thus it is associated to pathological conditions when found mutated. KMT2A germinal mutations are associated to Wiedemann-Steiner syndrome and also in patients with initial clinical diagnosis of several other chromatinopathies (i.e., Coffin-Siris syndromes, Kabuki syndrome, Cornelia De Lange syndrome, Rubinstein-Taybi syndrome), sharing an overlapping phenotype. On the other hand, KMT2A somatic mutations have been reported in several tumors, mainly blood malignancies. Due to its evolutionary conservation, the role of KMT2A in embryonic development, hematopoiesis and neurodevelopment has been explored in different animal models, and in recent decades, epigenetic treatments for disorders linked to KMT2A dysfunction have been extensively investigated. To note, pharmaceutical compounds acting on tumors characterized by KMT2A mutations have been formulated, and even nutritional interventions for chromatinopathies have become the object of study due to the role of microbiota in epigenetic regulation.

Keywords: KMT2A; chromatinopathies; epigenetics; tumors.

Figure 1

Representation of methylated lysines of histone tails. Lysines (yellow dots) of histone (H1, H2, H3, H4) tails can be mono-, bi-, tri-methylated (little lilac, blue and grey dots). The figure is not drawn to scale.

Figure 2

Representation of syndromes caused by mutations in genes coding for KMTs (Lysine methyltransferases) or KDMs (Lysisne demethylases). Syndromes (yellow inner ring) and the corresponding causative gene (coding for KMTs or KDMs, listed in the middle blue ring) are represented. The outer arcs indicate the site of epigenetic modification (NEDSID: Neurodevelopmental disorder with speech impairment and dysmorphic facies; EPEDD: Epilepsy, early-onset, with or without developmental delay).

Figure 3

Schematic view of KMT2A protein domains (below) and its main interactors (upper). KMT2A domains: MBM, high-affinity Menin-binding motif, residues 6–10; LBD, LEDGF-binding domain, residues 109–153; ATH1-2-3, AT-Hook1/2/3, residue 169–180, residues 217–227, residue 301–309; SNL1-2, nuclear-localization signal 1/2, residues 400–443, residues 1008–1106; CxxC, including: pre-CxxC region, residues 1149–1154, CxxC domain, residues 1147–1242, post-CxxC residues 1298–1337; PHD1-2-3-4, plant homology domain 1/2/3/4, residues 1431–1482, residues 1479–1533, residues 1566–1627, residues 1931–1978; BRD, bromodomain, residues 1703–1748; FYRN, FY-rich N-terminal domain, residues 2018–2074; TAD, transactivator domain, residues 2829–2883; FYRC, FY-rich C-terminal domain, residues 3666–3747; Win, WDR5 interaction motif, residues 3762–3773; SET, Su(Var)3-9 enhancer-of-zeste trithorax domain, residues 3829–2945. KMT2A has two sites for cutting by Taspase1: TCS1-2, taspase1 cleavage site 1/2, residue 2666–2670 and residues 2718–2722.

Figure 4

Comparison of typical facial features of (A) Wiedemann–Steiner syndrome [26]; (B) Coffin–Siris syndrome; (C) Kabuki syndrome; (D) Cornelia De Lange syndrome [27]; (E) Rubinstein–Taybi syndrome [28].

Figure 5

KMT2A somatic mutations in tumors ordered by percentage of positive cases (AACR Project GENIE).