KMT2A

{{short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox gene}} '''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.<ref name="pmid1720549">{{cite journal | vauthors = Ziemin-van der Poel S, McCabe NR, Gill HJ, Espinosa R, Patel Y, Harden A, Rubinelli P, Smith SD, LeBeau MM, Rowley JD | title = Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 23 | pages = 10735–9 | date = December 1991 | pmid = 1720549 | pmc = 53005 | doi = 10.1073/pnas.88.23.10735 | doi-access = free }}</ref>

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<ref name="9aaTAD">{{cite journal | vauthors = Goto NK, Zor T, Martinez-Yamout M, Dyson HJ, Wright PE|author-link4=Jane Dyson | title = Cooperativity in transcription factor binding to the coactivator CREB-binding protein (CBP). The mixed lineage leukemia protein (MLL) activation domain binds to an allosteric site on the KIX domain | journal = The Journal of Biological Chemistry | volume = 277 | issue = 45 | pages = 43168–74 | date = November 2002 | pmid = 12205094 | doi = 10.1074/jbc.M207660200 |s2cid=30354764 | url = http://www.tau.ac.il/lifesci/departments/biochem/members/zor/pdfs/Zor_JBC_MLL_2002.pdf | doi-access = free }}; {{cite journal | vauthors = Prasad R, Yano T, Sorio C, Nakamura T, Rallapalli R, Gu Y, Leshkowitz D, Croce CM, Canaani E | title = Domains with transcriptional regulatory activity within the ALL1 and AF4 proteins involved in acute leukemia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 26 | pages = 12160–4 | date = December 1995 | pmid = 8618864 | pmc = 40316 | doi = 10.1073/pnas.92.26.12160 | bibcode = 1995PNAS...9212160P | doi-access = free }}; {{cite journal | vauthors = Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ | title = MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein | journal = Molecular and Cellular Biology | volume = 21 | issue = 7 | pages = 2249–58 | date = April 2001 | pmid = 11259575 | pmc = 86859 | doi = 10.1128/MCB.21.7.2249-2258.2001 }}</ref> 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.

== 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 MLL1 enzyme trimethylates H3K4 (H3K4me3). It also upregulates mono- and dimethylation of H3K4.<ref>{{cite journal | vauthors = Del Rizzo PA, Trievel RC | title = Substrate and product specificities of SET domain methyltransferases | journal = Epigenetics | volume = 6 | issue = 9 | pages = 1059–67 | date = September 2011 | pmid = 21847010 | pmc = 3225744 | doi = 10.4161/epi.6.9.16069 }}</ref> This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C (~180 kDa) and MLL-N (~320 kDa).<ref>{{cite journal | vauthors = Takeda S, Chen DY, Westergard TD, Fisher JK, Rubens JA, Sasagawa S, Kan JT, Korsmeyer SJ, Cheng EH, Hsieh JJ | title = Proteolysis of MLL family proteins is essential for taspase1-orchestrated cell cycle progression | language = en | journal = Genes & Development | volume = 20 | issue = 17 | pages = 2397–409 | date = September 2006 | pmid = 16951254 | pmc = 1560414 | doi = 10.1101/gad.1449406 }}</ref><ref>{{cite journal | vauthors = Hsieh JJ, Ernst P, Erdjument-Bromage H, Tempst P, Korsmeyer SJ | title = Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization | language = en | journal = Molecular and Cellular Biology | volume = 23 | issue = 1 | pages = 186–94 | date = January 2003 | pmid = 12482972 | pmc = 140678 | doi = 10.1128/MCB.23.1.186-194.2003 }}</ref> 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.<ref name=":0">{{cite journal | vauthors = Jakovcevski M, Ruan H, Shen EY, Dincer A, Javidfar B, Ma Q, Peter CJ, Cheung I, Mitchell AC, Jiang Y, Lin CL, Pothula V, Stewart AF, Ernst P, Yao WD, Akbarian S | title = Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory | language = en | journal = The Journal of Neuroscience | volume = 35 | issue = 13 | pages = 5097–108 | date = April 2015 | pmid = 25834037 | pmc = 4380991 | doi = 10.1523/JNEUROSCI.3004-14.2015 }}</ref> Among them were ''Meis2'', a homeobox transcription factor critical for development of forebrain neurons<ref>{{cite journal | vauthors = Takahashi K, Liu FC, Oishi T, Mori T, Higo N, Hayashi M, Hirokawa K, Takahashi H | title = Expression of FOXP2 in the developing monkey forebrain: comparison with the expression of the genes FOXP1, PBX3, and MEIS2 | journal = The Journal of Comparative Neurology | volume = 509 | issue = 2 | pages = 180–9 | date = July 2008 | pmid = 18461604 | doi = 10.1002/cne.21740 | s2cid = 5166430 }}</ref><ref>{{cite journal | vauthors = Larsen KB, Lutterodt MC, Laursen H, Graem N, Pakkenberg B, Møllgård K, Møller M | title = Spatiotemporal distribution of PAX6 and MEIS2 expression and total cell numbers in the ganglionic eminence in the early developing human forebrain | journal = Developmental Neuroscience | volume = 32 | issue = 2 | pages = 149–62 | date = July 2010 | pmid = 20523026 | doi = 10.1159/000297602 | s2cid = 21973035 }}</ref> and ''Satb2'', a protein involved in neuronal differentiation.<ref>{{cite journal | vauthors = Britanova O, de Juan Romero C, Cheung A, Kwan KY, Schwark M, Gyorgy A, Vogel T, Akopov S, Mitkovski M, Agoston D, Sestan N, Molnár Z, Tarabykin V | title = Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex | journal = Neuron | volume = 57 | issue = 3 | pages = 378–92 | date = February 2008 | pmid = 18255031 | doi = 10.1016/j.neuron.2007.12.028 | s2cid = 9248058 | doi-access = free }}</ref>

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.<ref name="entrez">{{cite web | title = Entrez Gene: KMT2A lysine (K)-specific methyltransferase 2A | url = https://www.ncbi.nlm.nih.gov/gene/4297 }}</ref>

=== Cognition and emotion ===

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.<ref name=":0" />

=== Stem cells ===

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.<ref>{{cite journal |vauthors=Zhang H, Gayen S, Xiong J, Zhou B, Shanmugam AK, Sun Y, Karatas H, Liu L, Rao RC, Wang S, Nesvizhskii AI, Kalantry S, Dou Y |title=MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency |journal=Cell Stem Cell |volume=18 |issue=4 |pages=481–94 |year=2016 |pmid=26996599 |doi=10.1016/j.stem.2016.02.004 |pmc=4826731}}</ref>

== Structure ==

=== Gene ===

KMT2A gene has 37 exons and resides on chromosome 11 at q23.<ref name="entrez"/>

=== Protein ===

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.<ref name="pmid 12393701">{{cite journal | vauthors = Yokoyama A, Kitabayashi I, Ayton PM, Cleary ML, Ohki M | title = Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties | journal = Blood | volume = 100 | issue = 10 | pages = 3710–8 | date = November 2002 | pmid = 12393701 | doi = 10.1182/blood-2002-04-1015 | doi-access = free }}</ref> 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.<ref name="pmid 22500810">{{cite journal | vauthors = Mohan M, Herz HM, Shilatifard A | title = SnapShot: Histone lysine methylase complexes | journal = Cell | volume = 149 | issue = 2 | pages = 498–498.e1 | date = April 2012 | pmid = 22500810 | doi = 10.1016/j.cell.2012.03.025 | pmc=3711870}}</ref>

9aaTADs in the E protein family E2A and MLL binding to the KIX domain of CBP

== Clinical significance == Abnormal H3K4 trimethylation has been implicated in several neurological disorders such as autism.<ref name="Shulha HP 2011">{{cite journal | vauthors = Shulha HP, Cheung I, Whittle C, Wang J, Virgil D, Lin CL, Guo Y, Lessard A, Akbarian S, Weng Z | title = Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons | journal = Archives of General Psychiatry | volume = 69 | issue = 3 | pages = 314–24 | date = March 2012 | pmid = 22065254 | doi = 10.1001/archgenpsychiatry.2011.151 | doi-access = }}</ref> Humans with cognitive and neurodevelopmental disease often have dysregulation of H3K4 methylation in prefrontal cortex (PFC) neurons.<ref name="Shulha HP 2011"/><ref name="pmid17942719" /><ref>{{cite journal | vauthors = Shen E, Shulha H, Weng Z, Akbarian S | title = Regulation of histone H3K4 methylation in brain development and disease | language = en | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 369 | issue = 1652 | date = September 2014 | pmid = 25135975 | pmc = 4142035 | doi = 10.1098/rstb.2013.0514 | article-number=20130514}}</ref> It also may participate in the process of GAD67 downregulation in schizophrenia.<ref name="pmid17942719">{{cite journal | vauthors = Huang HS, Matevossian A, Whittle C, Kim SY, Schumacher A, Baker SP, Akbarian S | title = Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters | journal = The Journal of Neuroscience | volume = 27 | issue = 42 | pages = 11254–62 | date = October 2007 | pmid = 17942719 | doi = 10.1523/JNEUROSCI.3272-07.2007 | pmc = 6673022 | url = https://escholarship.umassmed.edu/infoservices/34 }}</ref>

MLL1 is required for the expression of senescence-associated secretory phenotype (SASP)-related genes and promotes increased inflammation.<ref name="pmid27259204">{{cite journal | vauthors=Booth LN, Brunet A | title=The Aging Epigenome | journal=Molecular Cell | volume=62 | issue=5 | pages=728–744 | year=2016 | doi= 10.1016/j.molcel.2016.05.013 | pmc=4917370 | pmid=27259204}}</ref>

Rearrangements of the MLL1 gene are associated with aggressive acute leukemias, both lymphoblastic and myeloid.<ref name="pmid15941828">{{cite journal | vauthors = Guenther MG, Jenner RG, Chevalier B, Nakamura T, Croce CM, Canaani E, Young RA | title = Global and Hox-specific roles for the MLL1 methyltransferase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 24 | pages = 8603–8 | date = June 2005 | pmid = 15941828 | pmc = 1150839 | doi = 10.1073/pnas.0503072102 | bibcode = 2005PNAS..102.8603G | doi-access = free }}</ref> Despite being an aggressive leukemia, the MLL1 rearranged sub-type had the lowest mutation rates reported for any cancer.<ref name="Andersson_2015">{{cite journal | vauthors = Andersson AK, Ma J, Wang J, Chen X, Gedman AL, Dang J, Nakitandwe J, Holmfeldt L, Parker M, Easton J, Huether R, Kriwacki R, Rusch M, Wu G, Li Y, Mulder H, Raimondi S, Pounds S, Kang G, Shi L, Becksfort J, Gupta P, Payne-Turner D, Vadodaria B, Boggs K, Yergeau D, Manne J, Song G, Edmonson M, Nagahawatte P, Wei L, Cheng C, Pei D, Sutton R, Venn NC, Chetcuti A, Rush A, Catchpoole D, Heldrup J, Fioretos T, Lu C, Ding L, Pui CH, Shurtleff S, Mullighan CG, Mardis ER, Wilson RK, Gruber TA, Zhang J, Downing JR | title = The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias | journal = Nature Genetics | volume = 47 | issue = 4 | pages = 330–7 | date = April 2015 | pmid = 25730765 | doi = 10.1038/ng.3230 | pmc=4553269}}</ref>

Mutations in MLL1 cause Wiedemann-Steiner syndrome and acute lymphoblastic leukemia.<ref>{{cite journal | vauthors = Mendelsohn BA, Pronold M, Long R, Smaoui N, Slavotinek AM | title = Advanced bone age in a girl with Wiedemann-Steiner syndrome and an exonic deletion in KMT2A (MLL) | journal = American Journal of Medical Genetics. Part A | volume = 164A | issue = 8 | pages = 2079–83 | date = August 2014 | pmid = 24818805 | doi = 10.1002/ajmg.a.36590 | s2cid = 20957397 }}</ref> 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.<ref name="Andersson_2015"/>

== Interactions ==

MLL (gene) has been shown to interact with: {{div col|colwidth=20em}} * ASH2L,<ref name = "pmid15199122" /> * CREBBP,<ref name = "pmid12205094">{{cite journal | vauthors = Goto NK, Zor T, Martinez-Yamout M, Dyson HJ, Wright PE | title = Cooperativity in transcription factor binding to the coactivator CREB-binding protein (CBP). The mixed lineage leukemia protein (MLL) activation domain binds to an allosteric site on the KIX domain | journal = The Journal of Biological Chemistry | volume = 277 | issue = 45 | pages = 43168–74 | date = November 2002 | pmid = 12205094 | doi = 10.1074/jbc.M207660200 | doi-access = free }}</ref><ref name = "pmid11259575">{{cite journal | vauthors = Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ | title = MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein | journal = Molecular and Cellular Biology | volume = 21 | issue = 7 | pages = 2249–58 | date = April 2001 | pmid = 11259575 | pmc = 86859 | doi = 10.1128/MCB.21.7.2249-2258.2001 }}</ref> * CTBP1,<ref name = "pmid12829790" /> * HDAC1,<ref name = "pmid12829790">{{cite journal | vauthors = Xia ZB, Anderson M, Diaz MO, Zeleznik-Le NJ | title = MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 14 | pages = 8342–7 | date = July 2003 | pmid = 12829790 | pmc = 166231 | doi = 10.1073/pnas.1436338100 | bibcode = 2003PNAS..100.8342X | doi-access = free }}</ref> * HCFC1,<ref name = "pmid15199122">{{cite journal | vauthors = Yokoyama A, Wang Z, Wysocka J, Sanyal M, Aufiero DJ, Kitabayashi I, Herr W, Cleary ML | title = Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression | journal = Molecular and Cellular Biology | volume = 24 | issue = 13 | pages = 5639–49 | date = July 2004 | pmid = 15199122 | pmc = 480881 | doi = 10.1128/MCB.24.13.5639-5649.2004 }}</ref> * MEN1,<ref name = "pmid15199122" /> * PPIE,<ref name = "pmid11313484">{{cite journal | vauthors = Fair K, Anderson M, Bulanova E, Mi H, Tropschug M, Diaz MO | title = Protein interactions of the MLL PHD fingers modulate MLL target gene regulation in human cells | journal = Molecular and Cellular Biology | volume = 21 | issue = 10 | pages = 3589–97 | date = May 2001 | pmid = 11313484 | pmc = 100280 | doi = 10.1128/MCB.21.10.3589-3597.2001 }}</ref> * PPP1R15A,<ref name = "pmid10490642">{{cite journal | vauthors = Adler HT, Chinery R, Wu DY, Kussick SJ, Payne JM, Fornace AJ, Tkachuk DC | title = Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins | journal = Molecular and Cellular Biology | volume = 19 | issue = 10 | pages = 7050–60 | date = October 1999 | pmid = 10490642 | pmc = 84700 | doi = 10.1128/mcb.19.10.7050}}</ref> * RBBP5,<ref name = "pmid15199122" /> and * WDR5.<ref name = "pmid15199122" /> {{Div col end}}

== References == {{Reflist|33em}}

== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = Marschalek R, Nilson I, Löchner K, Greim R, Siegler G, Greil J, Beck JD, Fey GH | title = The structure of the human ALL-1/MLL/HRX gene | journal = Leukemia & Lymphoma | volume = 27 | issue = 5–6 | pages = 417–28 | date = November 1997 | pmid = 9477123 | doi = 10.3109/10428199709058308 }} * {{cite journal | vauthors = Eguchi M, Eguchi-Ishimae M, Greaves M | title = The role of the MLL gene in infant leukemia | journal = International Journal of Hematology | volume = 78 | issue = 5 | pages = 390–401 | date = December 2003 | pmid = 14704031 | doi = 10.1007/BF02983811 | s2cid = 39901963 | doi-access = free }} * {{cite journal | vauthors = Daser A, Rabbitts TH | title = Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis | journal = Genes & Development | volume = 18 | issue = 9 | pages = 965–74 | date = May 2004 | pmid = 15132992 | doi = 10.1101/gad.1195504 | doi-access = free }} * {{cite journal | vauthors = Li ZY, Liu DP, Liang CC | title = New insight into the molecular mechanisms of MLL-associated leukemia | journal = Leukemia | volume = 19 | issue = 2 | pages = 183–90 | date = February 2005 | pmid = 15618964 | doi = 10.1038/sj.leu.2403602 | doi-access = free }} * {{cite journal | vauthors = Douet-Guilbert N, Morel F, Le Bris MJ, Sassolas B, Giroux JD, De Braekeleer M | title = Rearrangement of MLL in a patient with congenital acute monoblastic leukemia and granulocytic sarcoma associated with a t(1;11)(p36;q23) translocation | journal = Leukemia & Lymphoma | volume = 46 | issue = 1 | pages = 143–6 | date = January 2005 | pmid = 15621793 | doi = 10.1080/104281904000010783 | s2cid = 6686086 }} {{refend}}

== External links == * [http://omim.org/entry/159555 MLL OMIM Entry:] MYELOID/LYMPHOID OR MIXED LINEAGE LEUKEMIA GENE; '''MLL''' * {{MeshName|MLL+protein,+human}} * [https://web.archive.org/web/20111007123411/http://atlasgeneticsoncology.org/Genes/MLL.html Gene MLL] on the Atlas of Genetics and Oncology

Category:Epigenetics Category:Proteins Category:Transcription factors Category:Human proteins