Histone-lysineN-methyltransferase 2A, also known asacute lymphoblastic leukemia 1 (ALL-1),myeloid/lymphoid or mixed-lineage leukemia1 (MLL1), orzinc finger protein HRX (HRX), is anenzyme that in humans is encoded by theKMT2Agene.[5]
MLL1 is a histonemethyltransferase deemed a positive global regulator ofgene transcription. This protein belongs to the group ofhistone-modifying enzymes comprisingtransactivation domain 9aaTAD[6] and is involved in theepigenetic 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 andhematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, theSET domain, is responsible for itshistone H3 lysine 4 (H3K4) methyltransferase activity which mediateschromatin 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 enzymeTaspase 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 theHOX 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 wereMeis2, a homeobox transcription factor critical for development of forebrain neurons[11][12] andSatb2, a protein involved in neuronal differentiation.[13]
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 ofepiblast-derived stem cells, post-implantation epiblast derived stem cells which display pluripotency yet many recognizable differences from the traditionalembryonic 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 ofH3K4me1, the singlemethylation of thehistone 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 has over a dozen binding partners and is cleaved into two pieces, a largerN-terminal fragment, involved in gene repression, and a smallerC-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 othermethyltransferases, 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 inprefrontal cortex (PFC) neurons.[18][19][20] It also may participate in the process ofGAD67 downregulation inschizophrenia.[19]
Rearrangements of the MLL1 gene are associated with aggressive acuteleukemias, 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]
^Takahashi K, Liu FC, Oishi T, Mori T, Higo N, Hayashi M, et al. (July 2008). "Expression of FOXP2 in the developing monkey forebrain: comparison with the expression of the genes FOXP1, PBX3, and MEIS2".The Journal of Comparative Neurology.509 (2):180–9.doi:10.1002/cne.21740.PMID18461604.S2CID5166430.
^Larsen KB, Lutterodt MC, Laursen H, Graem N, Pakkenberg B, Møllgård K, et al. (July 2010). "Spatiotemporal distribution of PAX6 and MEIS2 expression and total cell numbers in the ganglionic eminence in the early developing human forebrain".Developmental Neuroscience.32 (2):149–62.doi:10.1159/000297602.PMID20523026.S2CID21973035.
^abShulha HP, Cheung I, Whittle C, Wang J, Virgil D, Lin CL, et al. (March 2012). "Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons".Archives of General Psychiatry.69 (3):314–24.doi:10.1001/archgenpsychiatry.2011.151.PMID22065254.
^Mendelsohn BA, Pronold M, Long R, Smaoui N, Slavotinek AM (August 2014). "Advanced bone age in a girl with Wiedemann-Steiner syndrome and an exonic deletion in KMT2A (MLL)".American Journal of Medical Genetics. Part A.164A (8):2079–83.doi:10.1002/ajmg.a.36590.PMID24818805.S2CID20957397.
Marschalek R, Nilson I, Löchner K, Greim R, Siegler G, Greil J, et al. (November 1997). "The structure of the human ALL-1/MLL/HRX gene".Leukemia & Lymphoma.27 (5–6):417–28.doi:10.3109/10428199709058308.PMID9477123.
Douet-Guilbert N, Morel F, Le Bris MJ, Sassolas B, Giroux JD, De Braekeleer M (January 2005). "Rearrangement of MLL in a patient with congenital acute monoblastic leukemia and granulocytic sarcoma associated with a t(1;11)(p36;q23) translocation".Leukemia & Lymphoma.46 (1):143–6.doi:10.1080/104281904000010783.PMID15621793.S2CID6686086.
