KMT2D: Difference between revisions

KMT2D
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	3UVK, 4ERQ, 4Z4P
Identifiers
Aliases	KMT2D, ALR, KABUK1, MLL2, MLL4, lysine methyltransferase 2D, histone-lysine methyltransferase 2D, TNRC21, AAD10, KMS, CAGL114
External IDs	OMIM: 602113; MGI: 2682319; HomoloGene: 86893; GeneCards: KMT2D; OMA:KMT2D - orthologs
Gene location (Human)
Chr.	Chromosome 12 (human)
End	49,060,794 bp
Gene location (Mouse)
Chr.	Chromosome 15 (mouse)
End	98,769,085 bp
RNA expression pattern
	Top expressed in
	internal globus pallidus; ; sural nerve; ; cardia; ; right uterine tube; ; gastrocnemius muscle; ; left uterine tube; ; subthalamic nucleus; ; renal medulla; ; right lobe of thyroid gland; ; anterior pituitary;
	Top expressed in
	secondary oocyte; ; superior frontal gyrus; ; lip; ; yolk sac; ; esophagus; ; thymus; ; cerebellar cortex; ; ganglionic eminence; ; spermatocyte; ; ascending aorta;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	metal ion binding; transferase activity; DNA binding; methyltransferase activity; protein binding; histone-lysine N-methyltransferase activity; histone methyltransferase activity (H3-K4 specific); DNA-binding transcription factor activity, RNA polymerase II-specific; transcription coactivator activity; histone binding;
Cellular component	nucleoplasm; MLL3/4 complex; nucleus; histone methyltransferase complex;
Biological process	positive regulation of intracellular estrogen receptor signaling pathway; transcription, DNA-templated; methylation; positive regulation of cell population proliferation; oogenesis; oocyte growth; response to estrogen; positive regulation of transcription by RNA polymerase II; histone H3-K4 methylation; regulation of transcription, DNA-templated; beta-catenin-TCF complex assembly; regulation of megakaryocyte differentiation; chromatin organization;
	Sources:Amigo / QuickGO
Orthologs
	8085
	381022
	ENSG00000167548
	ENSMUSG00000048154
	O14686
	Q6PDK2
	NM_003482
	NM_001033276; NM_001033388
	NP_003473
	NP_001028448
	Wikidata
View/Edit Human	View/Edit Mouse

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Revision as of 14:59, 10 May 2017

Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono- and di-methyltransferase.^[5] It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2F (or SET1A), and KMT2G (or SET1B). Each member of the family has a C-terminal SET domain that is responsible for the proteins’ enzymatic activities. KMT2D is homologous to Trithorax-related (Trr), which is a Trithorax-group protein.^[6] It is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues.^[7] KMT2D co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development.^[5] The protein also plays critical roles in regulating cell fate transition,^[5]^[8]^[9]^[10] metabolism,^[11]^[12] and tumor suppression.^[13]^[14]^[15]^[16] Mutations in KMT2D have been associated with Kabuki Syndrome,^[17] congenital heart disease,^[18] and various forms of cancer.^[19]

Structure

Gene

In mice, KMT2D is coded by the Kmt2d gene located on chromosome 15F1. Its transcript is 19,823 base pairs long and contains 55 exons and 54 introns.^[20] In humans, KMT2D is coded by the KMT2D gene located on chromosome 12q13.12. Its transcript is 19,419 base pairs long and contains 54 exons and 53 introns.^[21]

Protein

The mouse and human KMT2D proteins are 5,588 and 5,537 amino acids in length, respectively. Both species of the protein weigh about 600 kDa.^[20]^[21] KMT2D contains an enzymatically active C-terminal SET domain that is responsible for its methyltransferase activity.^[22] Near the SET domain are a plant homeotic domain (PHD) and FY-rich N/C-terminal (FYRN and FYRC) domains. The protein also contains six N-terminal PHDs, a high mobility group (HMG-I), and nine nuclear receptor interacting motifs (LXXLLs).^[19] It was shown that amino acids Y5426 and Y5512 are critical for the enzymatic activity of human KMT2D in vitro.^[23] In addition, data indicates that KMT2D’s H3K4 methyltransferase activity is required for maintaining the protein’s stability within cells.^[23]

Protein Complex

Several components of the KMT2D complex were first purified in 2003,^[24] and then the entire complex was identified in 2007.^[25]^[26]^[27]^[28] Along with KMT2D, the complex also contains ASH2L, RbBP5, WDR5, DPY30, NCOA6, UTX (also known as KDM6A), PA1, and PTIP. WDR5, RbBP5, ASH2L, and DPY30 form the four-subunit sub-complex WRAD, which is critical for H3K4 methyltransferase activity in all mammalian Set1-like histone methyltransferase complexes.^[29] UTX, the complex’s H3K27 demethylase, PTIP and PA1 are subunits that are unique to KMT2C and KMT2D.^[25]^[30]^[31] KMT2D acts as a scaffold protein within the complex; absence of KMT2D results in destabilization of UTX and collapse of the complex in cells.^[5]^[23]

Clinical significance

Two thirds of a sample of 53 cases of Kabuki Syndrome have a loss-of-function mutation in the KMT2D gene.^[32]

Mutations of this gene are common in various types of B-cell lymphoma ^[33] and are also associated with medulloblastoma ^[34] and pheochromocytoma.^[35]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000167548 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000048154 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b ^c ^d Lee, JE; Wang, C; Xu, S; Cho, YW; Wang, L; Feng, X; Baldridge, A; Sartorelli, V; Zhuang, L; Peng, W; Ge, K (24 December 2013). "H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation". eLife. 2: e01503. PMID 24368734.
^ Mohan, M; Herz, HM; Smith, ER; Zhang, Y; Jackson, J; Washburn, MP; Florens, L; Eissenberg, JC; Shilatifard, A (November 2011). "The COMPASS family of H3K4 methylases in Drosophila". Molecular and cellular biology. 31 (21): 4310–8. PMID 21875999.
^ Prasad, R; Zhadanov, AB; Sedkov, Y; Bullrich, F; Druck, T; Rallapalli, R; Yano, T; Alder, H; Croce, CM; Huebner, K; Mazo, A; Canaani, E (31 July 1997). "Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax". Oncogene. 15 (5): 549–60. PMID 9247308.
^ Wang, C; Lee, JE; Lai, B; Macfarlan, TS; Xu, S; Zhuang, L; Liu, C; Peng, W; Ge, K (18 October 2016). "Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition". Proceedings of the National Academy of Sciences of the United States of America. 113 (42): 11871–11876. PMID 27698142.
^ Dhar, SS; Lee, SH; Kan, PY; Voigt, P; Ma, L; Shi, X; Reinberg, D; Lee, MG (15 December 2012). "Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4". Genes & development. 26 (24): 2749–62. PMID 23249737.
^ Munehira, Y; Yang, Z; Gozani, O (11 October 2016). "Systematic Analysis of Known and Candidate Lysine Demethylases in the Regulation of Myoblast Differentiation". Journal of molecular biology. PMID 27732873.
^ Kim, DH; Rhee, JC; Yeo, S; Shen, R; Lee, SK; Lee, JW; Lee, S (March 2015). "Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice". Hepatology (Baltimore, Md.). 61 (3): 1012–23. PMID 25346535.
^ Kim, DH; Kim, J; Kwon, JS; Sandhu, J; Tontonoz, P; Lee, SK; Lee, S; Lee, JW (1 November 2016). "Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2". Cell reports. 17 (6): 1671–1682. PMID 27806304.
^ Zhang, J; Dominguez-Sola, D; Hussein, S; Lee, JE; Holmes, AB; Bansal, M; Vlasevska, S; Mo, T; Tang, H; Basso, K; Ge, K; Dalla-Favera, R; Pasqualucci, L (October 2015). "Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis". Nature medicine. 21 (10): 1190–8. PMID 26366712.
^ Lee, J; Kim, DH; Lee, S; Yang, QH; Lee, DK; Lee, SK; Roeder, RG; Lee, JW (26 May 2009). "A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4". Proceedings of the National Academy of Sciences of the United States of America. 106 (21): 8513–8. PMID 19433796.
^ Chen, C; Liu, Y; Rappaport, AR; Kitzing, T; Schultz, N; Zhao, Z; Shroff, AS; Dickins, RA; Vakoc, CR; Bradner, JE; Stock, W; LeBeau, MM; Shannon, KM; Kogan, S; Zuber, J; Lowe, SW (12 May 2014). "MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia". Cancer cell. 25 (5): 652–65. PMID 24794707.
^ Ortega-Molina, A; Boss, IW; Canela, A; Pan, H; Jiang, Y; Zhao, C; Jiang, M; Hu, D; Agirre, X; Niesvizky, I; Lee, JE; Chen, HT; Ennishi, D; Scott, DW; Mottok, A; Hother, C; Liu, S; Cao, XJ; Tam, W; Shaknovich, R; Garcia, BA; Gascoyne, RD; Ge, K; Shilatifard, A; Elemento, O; Nussenzweig, A; Melnick, AM; Wendel, HG (October 2015). "The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development". Nature medicine. 21 (10): 1199–208. PMID 26366710.
^ Ng, SB; Bigham, AW; Buckingham, KJ; Hannibal, MC; McMillin, MJ; Gildersleeve, HI; Beck, AE; Tabor, HK; Cooper, GM; Mefford, HC; Lee, C; Turner, EH; Smith, JD; Rieder, MJ; Yoshiura, K; Matsumoto, N; Ohta, T; Niikawa, N; Nickerson, DA; Bamshad, MJ; Shendure, J (September 2010). "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome". Nature genetics. 42 (9): 790–3. PMID 20711175.
^ Zaidi, S; Choi, M; Wakimoto, H; Ma, L; Jiang, J; Overton, JD; Romano-Adesman, A; Bjornson, RD; Breitbart, RE; Brown, KK; Carriero, NJ; Cheung, YH; Deanfield, J; DePalma, S; Fakhro, KA; Glessner, J; Hakonarson, H; Italia, MJ; Kaltman, JR; Kaski, J; Kim, R; Kline, JK; Lee, T; Leipzig, J; Lopez, A; Mane, SM; Mitchell, LE; Newburger, JW; Parfenov, M; Pe'er, I; Porter, G; Roberts, AE; Sachidanandam, R; Sanders, SJ; Seiden, HS; State, MW; Subramanian, S; Tikhonova, IR; Wang, W; Warburton, D; White, PS; Williams, IA; Zhao, H; Seidman, JG; Brueckner, M; Chung, WK; Gelb, BD; Goldmuntz, E; Seidman, CE; Lifton, RP (13 June 2013). "De novo mutations in histone-modifying genes in congenital heart disease". Nature. 498 (7453): 220–3. PMID 23665959.
^ ^a ^b Rao, RC; Dou, Y (June 2015). "Hijacked in cancer: the KMT2 (MLL) family of methyltransferases". Nature reviews. Cancer. 15 (6): 334–46. PMID 25998713.
^ ^a ^b "Transcript: Kmt2d-001 (ENSMUST00000023741.15) - Summary - Mus musculus - Ensembl genome browser 88". www.ensembl.org.
^ ^a ^b "Transcript: KMT2D-001 (ENST00000301067.11) - Summary - Homo sapiens - Ensembl genome browser 88". www.ensembl.org.
^ Ruthenburg, AJ; Allis, CD; Wysocka, J (12 January 2007). "Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark". Molecular cell. 25 (1): 15–30. PMID 17218268.
^ ^a ^b ^c Jang, Y; Wang, C; Zhuang, L; Liu, C; Ge, K (21 December 2016). "H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability". Journal of molecular biology. PMID 28013028.
^ Goo, YH; Sohn, YC; Kim, DH; Kim, SW; Kang, MJ; Jung, DJ; Kwak, E; Barlev, NA; Berger, SL; Chow, VT; Roeder, RG; Azorsa, DO; Meltzer, PS; Suh, PG; Song, EJ; Lee, KJ; Lee, YC; Lee, JW (January 2003). "Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins". Molecular and cellular biology. 23 (1): 140–9. PMID 12482968.
^ ^a ^b Cho, YW; Hong, T; Hong, S; Guo, H; Yu, H; Kim, D; Guszczynski, T; Dressler, GR; Copeland, TD; Kalkum, M; Ge, K (13 July 2007). "PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex". The Journal of biological chemistry. 282 (28): 20395–406. PMID 17500065.
^ Issaeva, I; Zonis, Y; Rozovskaia, T; Orlovsky, K; Croce, CM; Nakamura, T; Mazo, A; Eisenbach, L; Canaani, E (March 2007). "Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth". Molecular and cellular biology. 27 (5): 1889–903. PMID 17178841.
^ Lee, MG; Villa, R; Trojer, P; Norman, J; Yan, KP; Reinberg, D; Di Croce, L; Shiekhattar, R (19 October 2007). "Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination". Science (New York, N.Y.). 318 (5849): 447–50. PMID 17761849.
^ Patel, A; Vought, VE; Dharmarajan, V; Cosgrove, MS (21 November 2008). "A conserved arginine-containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex". The Journal of biological chemistry. 283 (47): 32162–75. PMID 18829457.
^ Ernst, P; Vakoc, CR (May 2012). "WRAD: enabler of the SET1-family of H3K4 methyltransferases". Briefings in functional genomics. 11 (3): 217–26. PMID 22652693.
^ Cho, YW; Hong, S; Ge, K (2012). "Affinity purification of MLL3/MLL4 histone H3K4 methyltransferase complex". Methods in molecular biology (Clifton, N.J.). 809: 465–72. PMID 22113294.
^ Hong, S; Cho, YW; Yu, LR; Yu, H; Veenstra, TD; Ge, K (20 November 2007). "Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases". Proceedings of the National Academy of Sciences of the United States of America. 104 (47): 18439–44. PMID 18003914.
^ Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J (September 2010). "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome". Nat. Genet. 42 (9): 790–3. doi:10.1038/ng.646. PMC 2930028. PMID 20711175.
^ Cite error: The named reference pmid21796119 was invoked but never defined (see the help page).
^ Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P (July 2012). "Dissecting the genomic complexity underlying medulloblastoma". Nature. 488 (7409): 100–5. doi:10.1038/nature11284. PMC 3662966. PMID 22832583.
^ Juhlin CC, Stenman A, Haglund F, Clark VE, Brown TC, Baranoski J, Bilguvar K, Goh G, Welander J, Svahn F, Rubinstein JC, Caramuta S, Yasuno K, Günel M, Bäckdahl M, Gimm O, Söderkvist P, Prasad ML, Korah R, Lifton RP, Carling T (May 2015). "Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene". Genes Chromosomes Cancer. 54 (9): 542–54. doi:10.1002/gcc.22267. PMC 4755142. PMID 26032282.

External links

GeneReviews/NCBI/NIH/UW entry on Kabuki syndrome, Kabuki Make-Up Syndrome, Niikawa-Kuroki Syndrome
MLL2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

This article on a gene on human chromosome 12 is a stub. You can help Wikipedia by expanding it.

^ Cite error: The named reference elife was invoked but never defined (see the help page).

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000167548 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000048154 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[elife-5] Lee, JE; Wang, C; Xu, S; Cho, YW; Wang, L; Feng, X; Baldridge, A; Sartorelli, V; Zhuang, L; Peng, W; Ge, K (24 December 2013). "H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation". eLife. 2: e01503. PMID 24368734.

[mohan-6] Mohan, M; Herz, HM; Smith, ER; Zhang, Y; Jackson, J; Washburn, MP; Florens, L; Eissenberg, JC; Shilatifard, A (November 2011). "The COMPASS family of H3K4 methylases in Drosophila". Molecular and cellular biology. 31 (21): 4310–8. PMID 21875999.

[prasad-7] Prasad, R; Zhadanov, AB; Sedkov, Y; Bullrich, F; Druck, T; Rallapalli, R; Yano, T; Alder, H; Croce, CM; Huebner, K; Mazo, A; Canaani, E (31 July 1997). "Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax". Oncogene. 15 (5): 549–60. PMID 9247308.

[Wang_2016_enhancer_priming-8] Wang, C; Lee, JE; Lai, B; Macfarlan, TS; Xu, S; Zhuang, L; Liu, C; Peng, W; Ge, K (18 October 2016). "Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition". Proceedings of the National Academy of Sciences of the United States of America. 113 (42): 11871–11876. PMID 27698142.

[dhar_trans-tail-9] Dhar, SS; Lee, SH; Kan, PY; Voigt, P; Ma, L; Shi, X; Reinberg, D; Lee, MG (15 December 2012). "Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4". Genes & development. 26 (24): 2749–62. PMID 23249737.

[munehira-10] Munehira, Y; Yang, Z; Gozani, O (11 October 2016). "Systematic Analysis of Known and Candidate Lysine Demethylases in the Regulation of Myoblast Differentiation". Journal of molecular biology. PMID 27732873.

[kim_2015-11] Kim, DH; Rhee, JC; Yeo, S; Shen, R; Lee, SK; Lee, JW; Lee, S (March 2015). "Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice". Hepatology (Baltimore, Md.). 61 (3): 1012–23. PMID 25346535.

[kim_2016-12] Kim, DH; Kim, J; Kwon, JS; Sandhu, J; Tontonoz, P; Lee, SK; Lee, S; Lee, JW (1 November 2016). "Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2". Cell reports. 17 (6): 1671–1682. PMID 27806304.

[zhang_2015_B_cell-13] Zhang, J; Dominguez-Sola, D; Hussein, S; Lee, JE; Holmes, AB; Bansal, M; Vlasevska, S; Mo, T; Tang, H; Basso, K; Ge, K; Dalla-Favera, R; Pasqualucci, L (October 2015). "Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis". Nature medicine. 21 (10): 1190–8. PMID 26366712.

[lee_2009_p53-14] Lee, J; Kim, DH; Lee, S; Yang, QH; Lee, DK; Lee, SK; Roeder, RG; Lee, JW (26 May 2009). "A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4". Proceedings of the National Academy of Sciences of the United States of America. 106 (21): 8513–8. PMID 19433796.

[chen_2014_mll3_tumor_suppressor-15] Chen, C; Liu, Y; Rappaport, AR; Kitzing, T; Schultz, N; Zhao, Z; Shroff, AS; Dickins, RA; Vakoc, CR; Bradner, JE; Stock, W; LeBeau, MM; Shannon, KM; Kogan, S; Zuber, J; Lowe, SW (12 May 2014). "MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia". Cancer cell. 25 (5): 652–65. PMID 24794707.

[ortega-molina-16] Ortega-Molina, A; Boss, IW; Canela, A; Pan, H; Jiang, Y; Zhao, C; Jiang, M; Hu, D; Agirre, X; Niesvizky, I; Lee, JE; Chen, HT; Ennishi, D; Scott, DW; Mottok, A; Hother, C; Liu, S; Cao, XJ; Tam, W; Shaknovich, R; Garcia, BA; Gascoyne, RD; Ge, K; Shilatifard, A; Elemento, O; Nussenzweig, A; Melnick, AM; Wendel, HG (October 2015). "The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development". Nature medicine. 21 (10): 1199–208. PMID 26366710.

[Ng_kabuki-17] Ng, SB; Bigham, AW; Buckingham, KJ; Hannibal, MC; McMillin, MJ; Gildersleeve, HI; Beck, AE; Tabor, HK; Cooper, GM; Mefford, HC; Lee, C; Turner, EH; Smith, JD; Rieder, MJ; Yoshiura, K; Matsumoto, N; Ohta, T; Niikawa, N; Nickerson, DA; Bamshad, MJ; Shendure, J (September 2010). "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome". Nature genetics. 42 (9): 790–3. PMID 20711175.

[zaidi_CHD-18] Zaidi, S; Choi, M; Wakimoto, H; Ma, L; Jiang, J; Overton, JD; Romano-Adesman, A; Bjornson, RD; Breitbart, RE; Brown, KK; Carriero, NJ; Cheung, YH; Deanfield, J; DePalma, S; Fakhro, KA; Glessner, J; Hakonarson, H; Italia, MJ; Kaltman, JR; Kaski, J; Kim, R; Kline, JK; Lee, T; Leipzig, J; Lopez, A; Mane, SM; Mitchell, LE; Newburger, JW; Parfenov, M; Pe'er, I; Porter, G; Roberts, AE; Sachidanandam, R; Sanders, SJ; Seiden, HS; State, MW; Subramanian, S; Tikhonova, IR; Wang, W; Warburton, D; White, PS; Williams, IA; Zhao, H; Seidman, JG; Brueckner, M; Chung, WK; Gelb, BD; Goldmuntz, E; Seidman, CE; Lifton, RP (13 June 2013). "De novo mutations in histone-modifying genes in congenital heart disease". Nature. 498 (7453): 220–3. PMID 23665959.

[rao_KMT2_review-19] Rao, RC; Dou, Y (June 2015). "Hijacked in cancer: the KMT2 (MLL) family of methyltransferases". Nature reviews. Cancer. 15 (6): 334–46. PMID 25998713.

[Mouse_ensemble-20] "Transcript: Kmt2d-001 (ENSMUST00000023741.15) - Summary - Mus musculus - Ensembl genome browser 88". www.ensembl.org.

[human_ensemble-21] "Transcript: KMT2D-001 (ENST00000301067.11) - Summary - Homo sapiens - Ensembl genome browser 88". www.ensembl.org.

[ruthenburg_review-22] Ruthenburg, AJ; Allis, CD; Wysocka, J (12 January 2007). "Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark". Molecular cell. 25 (1): 15–30. PMID 17218268.

[jang_YH-23] Jang, Y; Wang, C; Zhuang, L; Liu, C; Ge, K (21 December 2016). "H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability". Journal of molecular biology. PMID 28013028.

[goo_2003-24] Goo, YH; Sohn, YC; Kim, DH; Kim, SW; Kang, MJ; Jung, DJ; Kwak, E; Barlev, NA; Berger, SL; Chow, VT; Roeder, RG; Azorsa, DO; Meltzer, PS; Suh, PG; Song, EJ; Lee, KJ; Lee, YC; Lee, JW (January 2003). "Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins". Molecular and cellular biology. 23 (1): 140–9. PMID 12482968.

[cho_PTIP-25] Cho, YW; Hong, T; Hong, S; Guo, H; Yu, H; Kim, D; Guszczynski, T; Dressler, GR; Copeland, TD; Kalkum, M; Ge, K (13 July 2007). "PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex". The Journal of biological chemistry. 282 (28): 20395–406. PMID 17500065.

[Issaeva_2007-26] Issaeva, I; Zonis, Y; Rozovskaia, T; Orlovsky, K; Croce, CM; Nakamura, T; Mazo, A; Eisenbach, L; Canaani, E (March 2007). "Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth". Molecular and cellular biology. 27 (5): 1889–903. PMID 17178841.

[Lee_2007-27] Lee, MG; Villa, R; Trojer, P; Norman, J; Yan, KP; Reinberg, D; Di Croce, L; Shiekhattar, R (19 October 2007). "Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination". Science (New York, N.Y.). 318 (5849): 447–50. PMID 17761849.

[patel_2008-28] Patel, A; Vought, VE; Dharmarajan, V; Cosgrove, MS (21 November 2008). "A conserved arginine-containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex". The Journal of biological chemistry. 283 (47): 32162–75. PMID 18829457.

[29] Ernst, P; Vakoc, CR (May 2012). "WRAD: enabler of the SET1-family of H3K4 methyltransferases". Briefings in functional genomics. 11 (3): 217–26. PMID 22652693.

[cho_2012-30] Cho, YW; Hong, S; Ge, K (2012). "Affinity purification of MLL3/MLL4 histone H3K4 methyltransferase complex". Methods in molecular biology (Clifton, N.J.). 809: 465–72. PMID 22113294.

[Hong_UTX-31] Hong, S; Cho, YW; Yu, LR; Yu, H; Veenstra, TD; Ge, K (20 November 2007). "Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases". Proceedings of the National Academy of Sciences of the United States of America. 104 (47): 18439–44. PMID 18003914.

[pmid20711175-32] Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J (September 2010). "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome". Nat. Genet. 42 (9): 790–3. doi:10.1038/ng.646. PMC 2930028. PMID 20711175.

[pmid21796119-33] Cite error: The named reference pmid21796119 was invoked but never defined (see the help page).

[34] Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P (July 2012). "Dissecting the genomic complexity underlying medulloblastoma". Nature. 488 (7409): 100–5. doi:10.1038/nature11284. PMC 3662966. PMID 22832583.

[35] Juhlin CC, Stenman A, Haglund F, Clark VE, Brown TC, Baranoski J, Bilguvar K, Goh G, Welander J, Svahn F, Rubinstein JC, Caramuta S, Yasuno K, Günel M, Bäckdahl M, Gimm O, Söderkvist P, Prasad ML, Korah R, Lifton RP, Carling T (May 2015). "Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene". Genes Chromosomes Cancer. 54 (9): 542–54. doi:10.1002/gcc.22267. PMC 4755142. PMID 26032282.

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 '''Histone-lysine N-methyltransferase 2D''' (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono- and di-methyltransferase.<ref name="elife">{{cite journal|last1=Lee|first1=JE|last2=Wang|first2=C|last3=Xu|first3=S|last4=Cho|first4=YW|last5=Wang|first5=L|last6=Feng|first6=X|last7=Baldridge|first7=A|last8=Sartorelli|first8=V|last9=Zhuang|first9=L|last10=Peng|first10=W|last11=Ge|first11=K|title=H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation.|journal=eLife|date=24 December 2013|volume=2|pages=e01503|pmid=24368734}}</ref> It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2F (or SET1A), and KMT2G (or SET1B). Each member of the family has a C-terminal SET domain that is responsible for the proteins’ enzymatic activities. KMT2D is homologous to Trithorax-related (Trr), which is a [[Trithorax-group protein]].<ref name="mohan">{{cite journal|last1=Mohan|first1=M|last2=Herz|first2=HM|last3=Smith|first3=ER|last4=Zhang|first4=Y|last5=Jackson|first5=J|last6=Washburn|first6=MP|last7=Florens|first7=L|last8=Eissenberg|first8=JC|last9=Shilatifard|first9=A|title=The COMPASS family of H3K4 methylases in Drosophila.|journal=Molecular and cellular biology|date=November 2011|volume=31|issue=21|pages=4310-8|pmid=21875999}}</ref> It is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues.<ref name="prasad">{{cite journal|last1=Prasad|first1=R|last2=Zhadanov|first2=AB|last3=Sedkov|first3=Y|last4=Bullrich|first4=F|last5=Druck|first5=T|last6=Rallapalli|first6=R|last7=Yano|first7=T|last8=Alder|first8=H|last9=Croce|first9=CM|last10=Huebner|first10=K|last11=Mazo|first11=A|last12=Canaani|first12=E|title=Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax.|journal=Oncogene|date=31 July 1997|volume=15|issue=5|pages=549-60|pmid=9247308}}</ref> KMT2D co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development.<ref name="elife" /> The protein also plays critical roles in regulating cell fate transition,<ref name="elife" /><ref name="Wang 2016 enhancer priming">{{cite journal|last1=Wang|first1=C|last2=Lee|first2=JE|last3=Lai|first3=B|last4=Macfarlan|first4=TS|last5=Xu|first5=S|last6=Zhuang|first6=L|last7=Liu|first7=C|last8=Peng|first8=W|last9=Ge|first9=K|title=Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=18 October 2016|volume=113|issue=42|pages=11871-11876|pmid=27698142}}</ref><ref name="dhar trans-tail">{{cite journal|last1=Dhar|first1=SS|last2=Lee|first2=SH|last3=Kan|first3=PY|last4=Voigt|first4=P|last5=Ma|first5=L|last6=Shi|first6=X|last7=Reinberg|first7=D|last8=Lee|first8=MG|title=Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4.|journal=Genes & development|date=15 December 2012|volume=26|issue=24|pages=2749-62|pmid=23249737}}</ref><ref name="munehira">{{cite journal|last1=Munehira|first1=Y|last2=Yang|first2=Z|last3=Gozani|first3=O|title=Systematic Analysis of Known and Candidate Lysine Demethylases in the Regulation of Myoblast Differentiation.|journal=Journal of molecular biology|date=11 October 2016|pmid=27732873}}</ref> metabolism,<ref name="kim 2015">{{cite journal|last1=Kim|first1=DH|last2=Rhee|first2=JC|last3=Yeo|first3=S|last4=Shen|first4=R|last5=Lee|first5=SK|last6=Lee|first6=JW|last7=Lee|first7=S|title=Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice.|journal=Hepatology (Baltimore, Md.)|date=March 2015|volume=61|issue=3|pages=1012-23|pmid=25346535}}</ref><ref name="kim 2016">{{cite journal|last1=Kim|first1=DH|last2=Kim|first2=J|last3=Kwon|first3=JS|last4=Sandhu|first4=J|last5=Tontonoz|first5=P|last6=Lee|first6=SK|last7=Lee|first7=S|last8=Lee|first8=JW|title=Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2.|journal=Cell reports|date=1 November 2016|volume=17|issue=6|pages=1671-1682|pmid=27806304}}</ref> and tumor suppression.<ref name="zhang 2015 B cell">{{cite journal|last1=Zhang|first1=J|last2=Dominguez-Sola|first2=D|last3=Hussein|first3=S|last4=Lee|first4=JE|last5=Holmes|first5=AB|last6=Bansal|first6=M|last7=Vlasevska|first7=S|last8=Mo|first8=T|last9=Tang|first9=H|last10=Basso|first10=K|last11=Ge|first11=K|last12=Dalla-Favera|first12=R|last13=Pasqualucci|first13=L|title=Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis.|journal=Nature medicine|date=October 2015|volume=21|issue=10|pages=1190-8|pmid=26366712}}</ref><ref name="lee 2009 p53">{{cite journal|last1=Lee|first1=J|last2=Kim|first2=DH|last3=Lee|first3=S|last4=Yang|first4=QH|last5=Lee|first5=DK|last6=Lee|first6=SK|last7=Roeder|first7=RG|last8=Lee|first8=JW|title=A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=26 May 2009|volume=106|issue=21|pages=8513-8|pmid=19433796}}</ref><ref name="chen 2014 mll3 tumor suppressor">{{cite journal|last1=Chen|first1=C|last2=Liu|first2=Y|last3=Rappaport|first3=AR|last4=Kitzing|first4=T|last5=Schultz|first5=N|last6=Zhao|first6=Z|last7=Shroff|first7=AS|last8=Dickins|first8=RA|last9=Vakoc|first9=CR|last10=Bradner|first10=JE|last11=Stock|first11=W|last12=LeBeau|first12=MM|last13=Shannon|first13=KM|last14=Kogan|first14=S|last15=Zuber|first15=J|last16=Lowe|first16=SW|title=MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia.|journal=Cancer cell|date=12 May 2014|volume=25|issue=5|pages=652-65|pmid=24794707}}</ref><ref name="ortega-molina">{{cite journal|last1=Ortega-Molina|first1=A|last2=Boss|first2=IW|last3=Canela|first3=A|last4=Pan|first4=H|last5=Jiang|first5=Y|last6=Zhao|first6=C|last7=Jiang|first7=M|last8=Hu|first8=D|last9=Agirre|first9=X|last10=Niesvizky|first10=I|last11=Lee|first11=JE|last12=Chen|first12=HT|last13=Ennishi|first13=D|last14=Scott|first14=DW|last15=Mottok|first15=A|last16=Hother|first16=C|last17=Liu|first17=S|last18=Cao|first18=XJ|last19=Tam|first19=W|last20=Shaknovich|first20=R|last21=Garcia|first21=BA|last22=Gascoyne|first22=RD|last23=Ge|first23=K|last24=Shilatifard|first24=A|last25=Elemento|first25=O|last26=Nussenzweig|first26=A|last27=Melnick|first27=AM|last28=Wendel|first28=HG|title=The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.|journal=Nature medicine|date=October 2015|volume=21|issue=10|pages=1199-208|pmid=26366710}}</ref> Mutations in KMT2D have been associated with Kabuki Syndrome,<ref name="Ng kabuki">{{cite journal|last1=Ng|first1=SB|last2=Bigham|first2=AW|last3=Buckingham|first3=KJ|last4=Hannibal|first4=MC|last5=McMillin|first5=MJ|last6=Gildersleeve|first6=HI|last7=Beck|first7=AE|last8=Tabor|first8=HK|last9=Cooper|first9=GM|last10=Mefford|first10=HC|last11=Lee|first11=C|last12=Turner|first12=EH|last13=Smith|first13=JD|last14=Rieder|first14=MJ|last15=Yoshiura|first15=K|last16=Matsumoto|first16=N|last17=Ohta|first17=T|last18=Niikawa|first18=N|last19=Nickerson|first19=DA|last20=Bamshad|first20=MJ|last21=Shendure|first21=J|title=Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.|journal=Nature genetics|date=September 2010|volume=42|issue=9|pages=790-3|pmid=20711175}}</ref> congenital heart disease,<ref name="zaidi CHD">{{cite journal|last1=Zaidi|first1=S|last2=Choi|first2=M|last3=Wakimoto|first3=H|last4=Ma|first4=L|last5=Jiang|first5=J|last6=Overton|first6=JD|last7=Romano-Adesman|first7=A|last8=Bjornson|first8=RD|last9=Breitbart|first9=RE|last10=Brown|first10=KK|last11=Carriero|first11=NJ|last12=Cheung|first12=YH|last13=Deanfield|first13=J|last14=DePalma|first14=S|last15=Fakhro|first15=KA|last16=Glessner|first16=J|last17=Hakonarson|first17=H|last18=Italia|first18=MJ|last19=Kaltman|first19=JR|last20=Kaski|first20=J|last21=Kim|first21=R|last22=Kline|first22=JK|last23=Lee|first23=T|last24=Leipzig|first24=J|last25=Lopez|first25=A|last26=Mane|first26=SM|last27=Mitchell|first27=LE|last28=Newburger|first28=JW|last29=Parfenov|first29=M|last30=Pe'er|first30=I|last31=Porter|first31=G|last32=Roberts|first32=AE|last33=Sachidanandam|first33=R|last34=Sanders|first34=SJ|last35=Seiden|first35=HS|last36=State|first36=MW|last37=Subramanian|first37=S|last38=Tikhonova|first38=IR|last39=Wang|first39=W|last40=Warburton|first40=D|last41=White|first41=PS|last42=Williams|first42=IA|last43=Zhao|first43=H|last44=Seidman|first44=JG|last45=Brueckner|first45=M|last46=Chung|first46=WK|last47=Gelb|first47=BD|last48=Goldmuntz|first48=E|last49=Seidman|first49=CE|last50=Lifton|first50=RP|title=De novo mutations in histone-modifying genes in congenital heart disease.|journal=Nature|date=13 June 2013|volume=498|issue=7453|pages=220-3|pmid=23665959}}</ref> and various forms of cancer.<ref name="rao KMT2 review">{{cite journal|last1=Rao|first1=RC|last2=Dou|first2=Y|title=Hijacked in cancer: the KMT2 (MLL) family of methyltransferases.|journal=Nature reviews. Cancer|date=June 2015|volume=15|issue=6|pages=334-46|pmid=25998713}}</ref>
-== Nomenclature ==
+== Structure ==
+=== ''Gene'' ===
+In mice, KMT2D is coded by the ''Kmt2d'' gene located on chromosome 15F1. Its transcript is 19,823 base pairs long and contains 55 exons and 54 introns.<ref name="Mouse ensemble">{{cite web|title=Transcript: Kmt2d-001 (ENSMUST00000023741.15) - Summary - Mus musculus - Ensembl genome browser 88|url=http://www.ensembl.org/Mus_musculus/Transcript/Summary?db=core;g=ENSMUSG00000048154;r=15:98831669-98871204;t=ENSMUST00000023741|website=www.ensembl.org|language=en-gb}}</ref> In humans, KMT2D is coded by the ''KMT2D'' gene located on chromosome 12q13.12. Its transcript is 19,419 base pairs long and contains 54 exons and 53 introns.<ref name="human ensemble">{{cite web|title=Transcript: KMT2D-001 (ENST00000301067.11) - Summary - Homo sapiens - Ensembl genome browser 88|url=http://www.ensembl.org/Homo_sapiens/Transcript/Summary?db=core;g=ENSG00000167548;r=12:49018975-49059774;t=ENST00000301067|website=www.ensembl.org|language=en-gb}}</ref>
+=== ''Protein'' ===
-This gene is also generally known as MLL4 in the literature. This nomenclature has caused much confusion in the databases. Originally MLL2 was used to describe the sister gene of MLL1, which is also a trithorax-group histone methyltransferase.
+The mouse and human KMT2D proteins are 5,588 and 5,537 amino acids in length, respectively. Both species of the protein weigh about 600 kDa.<ref name="Mouse ensemble" /><ref name="human ensemble" /> KMT2D contains an enzymatically active C-terminal SET domain that is responsible for its methyltransferase activity.<ref name="ruthenburg review">{{cite journal|last1=Ruthenburg|first1=AJ|last2=Allis|first2=CD|last3=Wysocka|first3=J|title=Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark.|journal=Molecular cell|date=12 January 2007|volume=25|issue=1|pages=15-30|pmid=17218268}}</ref> Near the SET domain are a plant homeotic domain (PHD) and FY-rich N/C-terminal (FYRN and FYRC) domains. The protein also contains six N-terminal PHDs, a high mobility group (HMG-I), and nine nuclear receptor interacting motifs (LXXLLs).<ref name="rao KMT2 review" /> It was shown that amino acids Y5426 and Y5512 are critical for the enzymatic activity of human KMT2D ''in vitro''.<ref name="jang YH">{{cite journal|last1=Jang|first1=Y|last2=Wang|first2=C|last3=Zhuang|first3=L|last4=Liu|first4=C|last5=Ge|first5=K|title=H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability.|journal=Journal of molecular biology|date=21 December 2016|pmid=28013028}}</ref> In addition, data indicates that KMT2D’s H3K4 methyltransferase activity is required for maintaining the protein’s stability within cells.<ref name="jang YH" />
+=== ''Protein Complex'' ===
-The MLL1 gene was originally named ''MLL'' after myeloid/lymphoid or mixed-lineage leukemia cases. Its closest homologue is a very similar gene (not the gene described here), which is also called MLL2, but sometimes unfortunately called MLL4.
+Several components of the KMT2D complex were first purified in 2003,<ref name="goo 2003">{{cite journal|last1=Goo|first1=YH|last2=Sohn|first2=YC|last3=Kim|first3=DH|last4=Kim|first4=SW|last5=Kang|first5=MJ|last6=Jung|first6=DJ|last7=Kwak|first7=E|last8=Barlev|first8=NA|last9=Berger|first9=SL|last10=Chow|first10=VT|last11=Roeder|first11=RG|last12=Azorsa|first12=DO|last13=Meltzer|first13=PS|last14=Suh|first14=PG|last15=Song|first15=EJ|last16=Lee|first16=KJ|last17=Lee|first17=YC|last18=Lee|first18=JW|title=Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins.|journal=Molecular and cellular biology|date=January 2003|volume=23|issue=1|pages=140-9|pmid=12482968}}</ref> and then the entire complex was identified in 2007.<ref name="cho PTIP">{{cite journal|last1=Cho|first1=YW|last2=Hong|first2=T|last3=Hong|first3=S|last4=Guo|first4=H|last5=Yu|first5=H|last6=Kim|first6=D|last7=Guszczynski|first7=T|last8=Dressler|first8=GR|last9=Copeland|first9=TD|last10=Kalkum|first10=M|last11=Ge|first11=K|title=PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex.|journal=The Journal of biological chemistry|date=13 July 2007|volume=282|issue=28|pages=20395-406|pmid=17500065}}</ref><ref name="Issaeva 2007">{{cite journal|last1=Issaeva|first1=I|last2=Zonis|first2=Y|last3=Rozovskaia|first3=T|last4=Orlovsky|first4=K|last5=Croce|first5=CM|last6=Nakamura|first6=T|last7=Mazo|first7=A|last8=Eisenbach|first8=L|last9=Canaani|first9=E|title=Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth.|journal=Molecular and cellular biology|date=March 2007|volume=27|issue=5|pages=1889-903|pmid=17178841}}</ref><ref name="Lee 2007">{{cite journal|last1=Lee|first1=MG|last2=Villa|first2=R|last3=Trojer|first3=P|last4=Norman|first4=J|last5=Yan|first5=KP|last6=Reinberg|first6=D|last7=Di Croce|first7=L|last8=Shiekhattar|first8=R|title=Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination.|journal=Science (New York, N.Y.)|date=19 October 2007|volume=318|issue=5849|pages=447-50|pmid=17761849}}</ref><ref name="patel 2008">{{cite journal|last1=Patel|first1=A|last2=Vought|first2=VE|last3=Dharmarajan|first3=V|last4=Cosgrove|first4=MS|title=A conserved arginine-containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex.|journal=The Journal of biological chemistry|date=21 November 2008|volume=283|issue=47|pages=32162-75|pmid=18829457}}</ref> Along with KMT2D, the complex also contains ASH2L, RbBP5, WDR5, DPY30, NCOA6, UTX (also known as KDM6A), PA1, and PTIP. WDR5, RbBP5, ASH2L, and DPY30 form the four-subunit sub-complex WRAD, which is critical for H3K4 methyltransferase activity in all mammalian Set1-like histone methyltransferase complexes.<ref>{{cite journal|last1=Ernst|first1=P|last2=Vakoc|first2=CR|title=WRAD: enabler of the SET1-family of H3K4 methyltransferases.|journal=Briefings in functional genomics|date=May 2012|volume=11|issue=3|pages=217-26|pmid=22652693}}</ref> UTX, the complex’s H3K27 demethylase, PTIP and PA1 are subunits that are unique to KMT2C and KMT2D.<ref name="cho PTIP" /><ref name="cho 2012">{{cite journal|last1=Cho|first1=YW|last2=Hong|first2=S|last3=Ge|first3=K|title=Affinity purification of MLL3/MLL4 histone H3K4 methyltransferase complex.|journal=Methods in molecular biology (Clifton, N.J.)|date=2012|volume=809|pages=465-72|pmid=22113294}}</ref><ref name="Hong UTX">{{cite journal|last1=Hong|first1=S|last2=Cho|first2=YW|last3=Yu|first3=LR|last4=Yu|first4=H|last5=Veenstra|first5=TD|last6=Ge|first6=K|title=Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=20 November 2007|volume=104|issue=47|pages=18439-44|pmid=18003914}}</ref> KMT2D acts as a scaffold protein within the complex; absence of KMT2D results in destabilization of UTX and collapse of the complex in cells.<ref name="elife" /><ref name="jang YH" />
-The gene described here as MLL2 should properly be called MLL4 because along with its closely related homologue MLL3, it is closely related to a different Drosophila homologue of trithorax.
-The material included below refers to the trithorax group protein that is associated with MLL3 and a protein complex, not containing menin but including PTIP. It is listed as MLL2 but it should properly be called MLL4.
-It is now understood that its effect in lymphomagenesis is via the disruption of chromatin regulation.<ref name="pmid21796119">{{cite journal |vauthors=Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJ, Connors JM, Hirst M, Gascoyne RD, Marra MA | title = Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma | journal = Nature | volume = 476 | issue = 7360 | pages = 298–303 | date = August 2011 | pmid = 21796119 | pmc = 3210554 | doi = 10.1038/nature10351 }}</ref>
 == Clinical significance ==
 Two thirds of a sample of 53 cases of [[Kabuki Syndrome]] have a loss-of-function mutation in the KMT2D gene.<ref name="pmid20711175">{{cite journal |vauthors=Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J | title = Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome | journal = Nat. Genet. | volume = 42 | issue = 9 | pages = 790–3 | date = September 2010 | pmid = 20711175 | pmc = 2930028 | doi = 10.1038/ng.646 | url =  }}</ref>