Histone-lysine-methyltransferase 2A is an enzyme that in humans is encoded by the KMT2A gene. It is a transcriptional coactivator and histone methyltransferase whose SET domain catalyses methylation of lysine 4 on histone H3, a chromatin modification associated with transcriptional activation.
Histone-lysine-methyltransferase 2A regulates cell reproduction. It is active in generating blood cells (hematopoiesis) and during early development. KMT2A rearrangements are known genetic translocations of KMT2A and are a cause of acute leukemias and other cancers. Rearrangements of KMT2A are markers for diagnosis, prognosis, and treatment of acute leukemias. Mutations or dysregulation of the KMT2A protein product are also involved in several other types of cancers as well as developmental abnormalities such as Wiedemann-Steiner syndrome.
This protein belongs to the group of histone-modifying enzymes comprising transactivation domain 9aaTAD and is involved in the epigenetic maintenance of transcriptional memory. Its role as an epigenetic regulator of neuronal function is an ongoing area of research.
Gene
KMT2A gene has 37 exons and resides on chromosome 11 at q23.
Structure
The human KMT2A protein contains a total of 3,969 amino acid residues and contains the following motifs and domains (reading from the N-terminus to C-terminus):
| Order | Element | Type | Pfam accession | InterPro accession | Position (aa) | Function |
|---|---|---|---|---|---|---|
| 1 | Menin-binding motif (MBM) | Motif | — | — | 6–25 | Mediates direct interaction with menin (MEN1); this interaction is the target of menin inhibitors in KMT2A-rearranged leukemia |
| 2 | Integrase-binding motif 1 (IBM1) | Motif | — | — | 123–134 | Binds the integrase-binding domain of PSIP1/LEDGF, contributing to chromatin targeting |
| 3 | Integrase-binding motif 2 (IBM2) | Motif | — | — | 147–152 | Second PSIP1/LEDGF-binding motif, acting together with IBM1 |
| 4 | AT-hook 1 | DNA-binding motif | — | — | 169–180 | Binds AT-rich minor-groove DNA sequences |
| 5 | AT-hook 2 | DNA-binding motif | — | — | 217–227 | Second AT-rich DNA-binding motif |
| 6 | AT-hook 3 | DNA-binding motif | — | — | 301–309 | Third AT-rich DNA-binding motif |
| 7 | CXXC zinc finger domain | Domain | PF02008 | IPR002857 | 1148–1194 | Binds unmethylated CpG dinucleotides; typically retained in the N-terminal fragment of leukemogenic KMT2A fusion proteins |
| 8 | PHD finger (1) | Domain | PF00628 | IPR019787 | 1482–1530 | Chromatin-reader zinc finger; part of the PHD-finger cluster mediating protein–protein interactions |
| 9 | PHD finger (2) | Domain | PF00628 | IPR019787 | 1569–1624 | Second PHD finger of the cluster; contributes to histone/protein recognition |
| 10 | PHD-like zinc-binding domain | Domain | PF13771 | — | 1900–1978 | Atypical (extended) PHD-like zinc-binding module downstream of the PHD cluster |
| 11 | F/Y-rich N-terminal domain (FYRN) | Domain | PF05964 | IPR003888 | 2019–2074 | Pairs structurally with the downstream FYRC domain despite the large sequence separation |
| 12 | F/Y-rich C-terminal domain (FYRC) | Domain | PF05965 | IPR003889 | 3669–3748 | Folds together with FYRN to form a single structural unit; sits just upstream of the catalytic SET domain |
| 13 | SET domain | Domain | PF00856 | IPR001214 | 3840–3945 | C-terminal catalytic domain conferring H3K4 histone methyltransferase activity; lost from the oncogenic N-terminal fragment in KMT2A-rearranged fusions |
KMT2A has over a dozen binding partners and is cleaved into two pieces, a larger N-terminal fragment, involved in gene repression, and a smaller C-terminal fragment, which is a transcriptional activator. The cleavage, followed by the association of the two fragments, is necessary for KMT2A to be fully active. Like many other methyltransferases, the KMT2 family members exist in multisubunit nuclear complexes (human COMPASS), where other subunits also mediate the enzymatic activity.
Function
Transcriptional regulation
KMT2A gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. Enriched in the nucleus, the KMT2A enzyme trimethylates H3K4 (H3K4me3). It also upregulates mono- and dimethylation of H3K4. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C (~180 kDa) and MLL-N (~320 kDa). These fragments then assemble into different multi-protein complexes that regulate the transcription of specific target genes, including many of the HOX genes.
Transcriptome profiling after deletion of KMT2A in cortical neurons revealed decreased promoter-bound H3K4me3 peaks at 318 genes, with 31 of these having significantly decreased expression and promoter binding. Among them were Meis2, a homeobox transcription factor critical for development of forebrain neurons and Satb2, a protein involved in neuronal differentiation.
Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.
Cognition and emotion
KMT2A has been shown to be an important epigenetic regulator of complex behaviors. Rodent models of MLL1 dysfunction in forebrain neurons showed that conditional deletion results in elevated anxiety and defective cognition. Prefrontal cortex-specific knockout of KMT2A results in the same phenotypes, as well as working memory deficits.
Stem cells
KMT2A has been found to be an important regulator of epiblast-derived stem cells, post-implantation epiblast derived stem cells which display pluripotency yet many recognizable differences from the traditional embryonic stem cells derived from inner cell mass prior to implantation. Suppression of KMT2A expression was shown to be adequate for inducing ESC-like morphology and behavior within 72 hours of treatment. It has been proposed that the small molecule inhibitor MM-401, which was used to inhibit KMT2A, changes the distribution of H3K4me1, the single methylation of the histone H3 lysine 4, to be significantly downregulated at KMT2A targets thus leading to decreased expression of KMT2A targets, rather than a direct regulation of pluripotency core markers.
Clinical significance
The dysregulation of the KMT2A gene underlies a broad spectrum of human disease from cancer to developmental abnormalities.
Cancer
KMT2A is one of the most significant genes in cancer. Chromosomal rearrangements generating KMT2A fusion proteins with more than 90 partners (most commonly AFF1, MLLT1, MLLT3, and MLLT10). KMT2A gene rearrangements drive acute myeloid and acute lymphoblastic leukemias. Nearly 80% of infant acute lymphoblastic leukemia cases contain KMT2A gene rearrangements and KMT2A rearrangements are strongly associated with poor outcomes.
Related alterations such as KMT2A gene duplication (increased dosage of otherwise-normal KMT2A) and KMT2A-PTD ( partial tandem gene duplication that produces a functionally abnormal protein) likewise confer poor prognosis in myelodysplastic syndrome and acute myeloid leukemia. Amplification linked to a median survival of only 2–3 months. Beyond leukemia, KMT2A alterations occur in high-grade B-cell lymphoma and various solid tumors including sarcomas, pancreatic cancer, and colorectal cancer.
These findings have motivated the development of targeted therapeutic strategies against KMT2A's protein partners and interactions, including menin inhibitors such as revumenib, DOT1L inhibitors such as pinometostat, and agents targeting BRD4, LSD1, and WDR5.
Developmental abnormalities
Mutations in KMT2A cause Wiedemann-Steiner syndrome. Germline loss-of-function mutations in KMT2A cause Wiedemann–Steiner syndrome, an autosomal dominant disorder marked by intellectual disability, developmental delay, hypotonia, short stature, and characteristic craniofacial and skeletal features.
Inflammation
KMT2A is required for the expression of senescence-associated secretory phenotype (SASP)-related genes and promotes increased inflammation.
Neurological disorders
Abnormal H3K4 trimethylation has been implicated in several neurological disorders such as autism. Humans with cognitive and neurodevelopmental disease often have dysregulation of H3K4 methylation in prefrontal cortex (PFC) neurons. It also may participate in the process of GAD67 downregulation in schizophrenia.
