KMT2A

KMT2A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2AGH, 2J2S, 2JYI, 2KKF, 2KU7, 2KYU, 2LXS, 2LXT, 2MTN, 2W5Y, 2W5Z, 3EG6, 3EMH, 3LQI, 3LQJ, 3P4F, 3U85, 3U88, 4ESG, 4GQ6, 4NW3, 5F6L, 5F5E
Identifiers
Aliases	KMT2A, ALL-1, CXXC7, HRX, HTRX1, MLL, MLL/GAS7, MLL1, MLL1A, TET1-MLL, TRX1, WDSTS, MLL-AF9, lysine methyltransferase 2A, Histone-lysine N-methyltransferase HRX, ALL1, HTRX
External IDs	MGI: 96995; HomoloGene: 4338; GeneCards: KMT2A; OMA:KMT2A - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q23.3 Start 118,436,456 bp[1] End 118,526,832 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 A5.2|9 24.84 cM Start 44,714,652 bp[2] End 44,792,594 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ventricular zone epithelium of colon sural nerve ganglionic eminence Achilles tendon Brodmann area 23 bone marrow cells cerebellar vermis lateral nuclear group of thalamus external globus pallidus Top expressed in tail of embryo genital tubercle dorsomedial hypothalamic nucleus Rostral migratory stream CA3 field cingulate gyrus central gray substance of midbrain habenula neural layer of retina entorhinal cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function methyltransferase activity transferase activity DNA binding protein homodimerization activity minor groove of adenine-thymine-rich DNA binding DNA-binding transcription factor activity zinc ion binding chromatin binding metal ion binding core promoter sequence-specific DNA binding protein binding unmethylated CpG binding lysine-acetylated histone binding identical protein binding histone-lysine N-methyltransferase activity histone methyltransferase activity (H3-K4 specific) DNA-binding transcription factor activity, RNA polymerase II-specific RNA polymerase II cis-regulatory region sequence-specific DNA binding Cellular component nucleoplasm nucleus histone methyltransferase complex cytosol MLL1 complex Biological process visual learning response to potassium ion regulation of transcription, DNA-templated cognition positive regulation of transporter activity positive regulation of cellular response to drug response to light stimulus rhythmic process regulation of short-term neuronal synaptic plasticity histone H3-K4 trimethylation membrane depolarization regulation of histone H3-K4 methylation regulation of histone H3-K9 acetylation transcription by RNA polymerase II post-embryonic development peptidyl-lysine monomethylation spleen development circadian regulation of gene expression regulation of histone H3-K14 acetylation transcription, DNA-templated regulation of histone H3-K27 acetylation positive regulation of transcription, DNA-templated DNA methylation histone H3-K4 methylation methylation positive regulation of histone H3-K4 methylation exploration behavior embryonic hemopoiesis histone H3-K4 dimethylation regulation of gene expression homeostasis of number of cells within a tissue histone H4-K16 acetylation definitive hemopoiesis anterior/posterior pattern specification negative regulation of cell population proliferation apoptotic process regulation of megakaryocyte differentiation regulation of hematopoietic stem cell differentiation chromatin organization positive regulation of transcription by RNA polymerase II protein-containing complex assembly negative regulation of DNA methylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4297 214162 Ensembl ENSG00000118058 ENSMUSG00000002028 UniProt Q03164 P55200 RefSeq (mRNA) NM_001197104 NM_005933 NM_024891 NM_001081049 NM_001357549 RefSeq (protein) NP_001184033 NP_005924 NP_001344478 Location (UCSC) Chr 11: 118.44 – 118.53 Mb Chr 9: 44.71 – 44.79 Mb PubMed search [3] [4]
Wikidata
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Histone-lysine N-methyltransferase 2A, also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia 1 (MLL1), or zinc finger protein HRX (HRX), is an enzyme that in humans is encoded by the KMT2A gene.^[5]

MLL1 is a histone methyltransferase deemed a positive global regulator of gene transcription. This protein belongs to the group of histone-modifying enzymes comprising transactivation domain 9aaTAD^[6] 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.

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 MLL1 enzyme trimethylates H3K4 (H3K4me3). It also upregulates mono- and dimethylation of H3K4.^[7] This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C (~180 kDa) and MLL-N (~320 kDa).^[8][9] 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 MLL1 in cortical neurons revealed decreased promoter-bound H3K4me3 peaks at 318 genes, with 31 of these having significantly decreased expression and promoter binding.^[10] Among them were Meis2, a homeobox transcription factor critical for development of forebrain neurons^[11][12] and Satb2, a protein involved in neuronal differentiation.^[13]

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.^[14]

MLL1 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 MLL1 results in the same phenotypes, as well as working memory deficits.^[10]

MLL1 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 MLL1 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 MLL1, changes the distribution of H3K4me1, the single methylation of the histone H3 lysine 4, to be significantly downregulated at MLL1 targets thus leading to decreased expression of MLL1 targets, rather than a direct regulation of pluripotency core markers.^[15]

KMT2A gene has 37 exons and resides on chromosome 11 at q23.^[14]

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.^[16] 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.^[17]

Abnormal H3K4 trimethylation has been implicated in several neurological disorders such as autism.^[18] Humans with cognitive and neurodevelopmental disease often have dysregulation of H3K4 methylation in prefrontal cortex (PFC) neurons.^[18][19][20] It also may participate in the process of GAD67 downregulation in schizophrenia.^[19]

MLL1 is required for the expression of senescence-associated secretory phenotype (SASP)-related genes and promotes increased inflammation.^[21]

Rearrangements of the MLL1 gene are associated with aggressive acute leukemias, both lymphoblastic and myeloid.^[22] Despite being an aggressive leukemia, the MLL1 rearranged sub-type had the lowest mutation rates reported for any cancer.^[23]

Mutations in MLL1 cause Wiedemann-Steiner syndrome and acute lymphoblastic leukemia.^[24] The leukemia cells of up to 80 percent of infants with ALL-1 have a chromosomal rearrangement that fuses the MLL1 gene to a gene on a different chromosome.^[23]

MLL (gene) has been shown to interact with:

• MLL OMIM Entry: MYELOID/LYMPHOID OR MIXED LINEAGE LEUKEMIA GENE; MLL
• MLL+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Gene MLL on the Atlas of Genetics and Oncology