KMT2D

KMT2D
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesKMT2D, ALR, KABUK1, MLL2, MLL4, lysine methyltransferase 2D, histone-lysine methyltransferase 2D, TNRC21, AAD10, KMS, CAGL114
External IDsOMIM: 602113; MGI: 2682319; HomoloGene: 86893; GeneCards: KMT2D; OMA:KMT2D - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8085

381022

Ensembl

ENSG00000167548

ENSMUSG00000048154

UniProt

O14686

Q6PDK2

RefSeq (mRNA)

NM_003482

NM_001033276
NM_001033388

RefSeq (protein)

NP_003473

NP_001028448

Location (UCSC)Chr 12: 49.02 – 49.06 MbChr 15: 98.73 – 98.77 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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-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).

KMT2D is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues.[6] The protein co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development.[5] It also plays critical roles in regulating cell fate transition,[5][7][8][9] metabolism,[10][11] and tumor suppression.[12][13][14][15]

Mutations in KMT2D cause human genetic conditions including Kabuki syndrome,[16] another distinct congenital malformations disorder[17] and various forms of cancer.[18]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000167548 – Ensembl, May 2017
  2. ^ a b c 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.
  5. ^ a b c Lee JE, Wang C, Xu S, Cho YW, Wang L, Feng X, et al. (December 2013). "H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation". eLife. 2: e01503. arXiv:1311.7328. doi:10.7554/eLife.01503. PMC 3869375. PMID 24368734.
  6. ^ Prasad R, Zhadanov AB, Sedkov Y, Bullrich F, Druck T, Rallapalli R, et al. (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. doi:10.1038/sj.onc.1201211. PMID 9247308. S2CID 31178216.
  7. ^ Wang C, Lee JE, Lai B, Macfarlan TS, Xu S, Zhuang L, Liu C, Peng W, Ge K (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. Bibcode:2016PNAS..11311871W. doi:10.1073/pnas.1606857113. PMC 5081576. PMID 27698142.
  8. ^ Dhar SS, Lee SH, Kan PY, Voigt P, Ma L, Shi X, Reinberg D, Lee MG (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. doi:10.1101/gad.203356.112. PMC 3533079. PMID 23249737.
  9. ^ Munehira Y, Yang Z, Gozani O (October 2016). "Systematic Analysis of Known and Candidate Lysine Demethylases in the Regulation of Myoblast Differentiation". Journal of Molecular Biology. 429 (13): 2055–2065. doi:10.1016/j.jmb.2016.10.004. PMC 5388604. PMID 27732873.
  10. ^ 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. 61 (3): 1012–23. doi:10.1002/hep.27578. PMC 4474368. PMID 25346535.
  11. ^ Kim DH, Kim J, Kwon JS, Sandhu J, Tontonoz P, Lee SK, Lee S, Lee JW (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. doi:10.1016/j.celrep.2016.10.023. PMID 27806304.
  12. ^ Zhang J, Dominguez-Sola D, Hussein S, Lee JE, Holmes AB, Bansal M, et al. (October 2015). "Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis". Nature Medicine. 21 (10): 1190–8. doi:10.1038/nm.3940. PMC 5145002. PMID 26366712.
  13. ^ Lee J, Kim DH, Lee S, Yang QH, Lee DK, Lee SK, Roeder RG, Lee JW (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. Bibcode:2009PNAS..106.8513L. doi:10.1073/pnas.0902873106. PMC 2689008. PMID 19433796.
  14. ^ 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 (May 2014). "MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia". Cancer Cell. 25 (5): 652–65. doi:10.1016/j.ccr.2014.03.016. PMC 4206212. PMID 24794707.
  15. ^ Ortega-Molina A, Boss IW, Canela A, Pan H, Jiang Y, Zhao C, et al. (October 2015). "The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development". Nature Medicine. 21 (10): 1199–208. doi:10.1038/nm.3943. PMC 4676270. PMID 26366710.
  16. ^ Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. (September 2010). "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome". Nature Genetics. 42 (9): 790–793. doi:10.1038/ng.646. PMC 2930028. PMID 20711175.
  17. ^ Cuvertino S, Hartill V, Colyer A, Garner T, Nair N, Al-Gazali L, et al. (May 2020). "A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome". Genetics in Medicine. 22 (5): 867–877. doi:10.1038/s41436-019-0743-3. PMC 7200597. PMID 31949313.
  18. ^ Rao RC, Dou Y (June 2015). "Hijacked in cancer: the KMT2 (MLL) family of methyltransferases". Nature Reviews. Cancer. 15 (6): 334–346. doi:10.1038/nrc3929. PMC 4493861. PMID 25998713.