Biology:KMT2D

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] 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.[2] The protein co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development.[1] It also plays critical roles in regulating cell fate transition,[1][3][4][5] metabolism,[6][7] and tumor suppression.[8][9][10][11]

Mutations in KMT2D cause human genetic conditions including Kabuki syndrome,[12] another distinct congenital malformations disorder[13] and various forms of cancer.[14]

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.[15]

In humans, KMT2D is coded by the KMT2D gene located on chromosome 12q13.12. It's transcript is 19,419 base pairs long and contains 54 exons and 53 introns.[16]

Protein

KMT2D is homologous to Trithorax-related (Trr), which is a Trithorax-group protein.[17] 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.[15][16] KMT2D contains an enzymatically active C-terminal SET domain that is responsible for its methyltransferase activity and maintaining protein stability in cells.[18] 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).[14] It was shown that amino acids Y5426 and Y5512 are critical for the enzymatic activity of human KMT2D in vitro.[19] In addition, mutation of Y5477 in mouse KMT2D, which corresponds to Y5426 in human KMT2D, resulted in the inactivation of KMT2D's enzymatic activity in embryonic stem cells.[20] Depletion of cellular H3K4 methylation reduces KMT2D levels, indicating that the protein's stability could be regulated by cellular H3K4 methylation.[19]

Protein complex

Several components of the KMT2D complex were first purified in 2003,[21] and then the entire complex was identified in 2007.[22][23][24][25] 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.[26] WDR5 binds directly with FYRN/FYRC domains of C-terminal SET domain-containing fragments of human KMT2C and KMT2D.[22] UTX, the complex’s H3K27 demethylase, PTIP, and PA1 are subunits that are unique to KMT2C and KMT2D.[22][27][28] KMT2D acts as a scaffold protein within the complex; absence of KMT2D results in destabilization of UTX and collapse of the complex in cells.[1][19]

Enhancer regulation

KMT2D is a major enhancer mono-methyltransferase and has partial functional redundancy with KMT2C.[1][3] The protein selectively binds enhancer regions based on type of cell and stage of differentiation. During differentiation, lineage determining transcription factors recruit KMT2D to establish cell-type specific enhancers. For example, CCAAT/enhancer-binding protein β (C/EBPβ), an early adipogenic transcription factor, recruits and requires KMT2D to establish a subset of adipogenic enhancers during adipogenesis. Depletion of KMT2D prior to differentiation prevents the accumulation of H3K4 mono-methylation (H3K4me1), H3K27 acetylation, the transcriptional coactivator Mediator, and RNA polymerase II on enhancers, resulting in severe defects in gene expression and cell differentiation.[1] KMT2C and KMT2D also identify super-enhancers and are required for formation of super-enhancers during cell differentiation.[29] Mechanistically, KMT2C and KMT2D are required for the binding of H3K27 acetyltransferases CREB-binding protein (CBP) and/or p300 on enhancers, enhancer activation, and enhancer-promotor looping prior to gene transcription.[1][29] The KMT2C and KMT2D proteins, rather than the KMT2C and KMT2D-mediated H3K4me1, control p300 recruitment to enhancers, enhancer activation, and transcription from promoters in embryonic stem cells.[3]

Functions

Development

Whole-body knockout of Kmt2d in mice results in early embryonic lethality.[1] Targeted knockout of Kmt2d in precursors cells of brown adipocytes and myocytes results in decreases in brown adipose tissue and muscle mass in mice, indicating that KMT2D is required for adipose and muscle tissue development.[1] In the hearts of mice, a single copy of the Kmt2d gene is sufficient for normal heart development.[30] Complete loss of Kmt2d in cardiac precursors and myocardium leads to severe cardiac defects and early embryonic lethality. KMT2D mediated mono- and di-methylation is required for maintaining necessary gene expression programs during heart development. Knockout studies in mice also show that KMT2D is required for proper B-cell development.[8]

Cell fate transition

KMT2D is partially functionally redundant with KMT2C and is required for cell differentiation in culture.[1][3] KMT2D regulates the induction of adipogenic and myogenic genes and is required for cell-type specific gene expression during differentiation. KMT2C and KMT2D are essential for adipogenesis and myogenesis.[1] Similar functions are seen in neuronal and osteoblast differentiation.[4][5] KMT2D facilitates cell fate transition by priming enhancers (through H3K4me1) for p300-mediated activation. For p300 to bind the enhancer, the physical presence of KMT2D, and not just the KMT2D-mediated H3K4me1, is required. However, KMT2D is dispensable for maintaining embryonic stem cell and somatic cell identity.[3]

Metabolism

KMT2D is partially functionally redundant with KMT2C in the liver as well. Heterozygous Kmt2d+/- mice exhibit enhanced glucose tolerance and insulin sensitivity and increased serum bile acid.[6] KMT2C and KMT2D are significant epigenetic regulators of the hepatic circadian clock and are co-activators of the circadian transcription factors retinoid-related orphan receptor (ROR)-α and -γ.[6] In mice, KMT2D also acts as a coactivator of PPARγ within the liver to direct over-nutrition induced steatosis. Heterozygous Kmt2d+/- mice exhibit resistance to over-nutrition induced hepatic steatosis.[7]

Tumor suppression

KMT2C and KMT2D along with NCOA6 act as coactivators of p53, a well-established tumor suppressor and transcription factor, and are necessary for endogenous expression of p53 in response to doxorubicin, a DNA damaging agent.[9] KMT2C and KMT2D have also been implicated with tumor suppressor roles in acute myeloid leukemia, follicular lymphoma, and diffuse large B cell lymphoma.[8][10][11] Knockout of Kmt2d in mice negatively affects the expression of tumor suppressor genes TNFAIP3, SOCS3, and TNFRSF14.[11]

Conversely, KMT2D deficiency in several breast and colon cancer cell lines leads to reduced proliferation.[31][32][33] Increased KMT2D was shown to facilitate chromatin opening and recruitment of transcription factors, including estrogen receptor (ER), in ER-positive breast cancer cells.[34] Thus, KMT2D may have diverse effects on tumor suppression in different cell types.

Clinical significance

Germline heterozygous loss of function mutations in KMT2D, also known as MLL2 in humans, cause Kabuki syndrome type 1[12] with mutational occurrence rates between 56% and 75%.[35][36][37][38] Mosaic mutations and intragenic deletions and duplications have also been described in this condition.[39] Type 1 Kabuki syndrome is characterised by developmental delay, intellectual disability, postnatal dwarfism, recognizable facial dysmorphism (reminiscent of the make-up of actors of Kabuki theatre), a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy.[40] Note that variants in a functionally related gene, KDM6A, cause Kabuki syndrome type 2 that is an X-linked condition, shares several clinical features with Kabuki syndrome type 1 but phenotypically is a much more variable condition.[41]

Germline heterozygous missense variants in exon 38 or 39 of the KMT2D gene cause another rare distinct multiple malformation disorder characterized by choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities.[13]

Congenital heart disease has been associated with an excess of mutations in genes that regulate H3K4 methylation, including KMT2D.[42]

Somatic frameshift and nonsense mutations in the SET and PHD domains affect 37% and 60%, respectively, of the total KMT2D mutations in cancers.[14] Cancers with somatic mutations in KMT2D occur most commonly in the brain, lymph nodes, blood, lungs, large intestine, and endometrium.[14] These cancers include medulloblastoma,[43][44][45] pheochromocytoma,[46] non-Hodgkin lymphomas,[47] cutaneous T-cell lymphoma, Sézary syndrome,[48] bladder, lung, and endometrial carcinomas,[49] esophageal squamous cell carcinoma,[50][51][52] pancreatic cancer,[53] and prostate cancer.[54]

Note

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 "H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation". eLife 2: e01503. December 2013. doi:10.7554/eLife.01503. PMID 24368734. 
  2. ↑ "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. July 1997. doi:10.1038/sj.onc.1201211. PMID 9247308. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "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. October 2016. doi:10.1073/pnas.1606857113. PMID 27698142. Bibcode: 2016PNAS..11311871W. 
  4. ↑ 4.0 4.1 "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. December 2012. doi:10.1101/gad.203356.112. PMID 23249737. 
  5. ↑ 5.0 5.1 "Systematic Analysis of Known and Candidate Lysine Demethylases in the Regulation of Myoblast Differentiation". Journal of Molecular Biology 429 (13): 2055–2065. October 2016. doi:10.1016/j.jmb.2016.10.004. PMID 27732873. 
  6. ↑ 6.0 6.1 6.2 "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. March 2015. doi:10.1002/hep.27578. PMID 25346535. 
  7. ↑ 7.0 7.1 "Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2". Cell Reports 17 (6): 1671–1682. November 2016. doi:10.1016/j.celrep.2016.10.023. PMID 27806304. 
  8. ↑ 8.0 8.1 8.2 "Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis". Nature Medicine 21 (10): 1190–8. October 2015. doi:10.1038/nm.3940. PMID 26366712. 
  9. ↑ 9.0 9.1 "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. May 2009. doi:10.1073/pnas.0902873106. PMID 19433796. Bibcode: 2009PNAS..106.8513L. 
  10. ↑ 10.0 10.1 "MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia". Cancer Cell 25 (5): 652–65. May 2014. doi:10.1016/j.ccr.2014.03.016. PMID 24794707. 
  11. ↑ 11.0 11.1 11.2 "The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development". Nature Medicine 21 (10): 1199–208. October 2015. doi:10.1038/nm.3943. PMID 26366710. 
  12. ↑ 12.0 12.1 "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome". Nature Genetics 42 (9): 790–793. September 2010. doi:10.1038/ng.646. PMID 20711175. 
  13. ↑ 13.0 13.1 "A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome". Genetics in Medicine 22 (5): 867–877. May 2020. doi:10.1038/s41436-019-0743-3. PMID 31949313. 
  14. ↑ 14.0 14.1 14.2 14.3 "Hijacked in cancer: the KMT2 (MLL) family of methyltransferases". Nature Reviews. Cancer 15 (6): 334–346. June 2015. doi:10.1038/nrc3929. PMID 25998713. 
  15. ↑ 15.0 15.1 "Transcript: Kmt2d-001 (ENSMUST00000023741.15) - Summary - Mus musculus - Ensembl genome browser 88" (in en-gb). http://www.ensembl.org/Mus_musculus/Transcript/Summary?db=core;g=ENSMUSG00000048154;r=15:98831669-98871204;t=ENSMUST00000023741. 
  16. ↑ 16.0 16.1 "Transcript: KMT2D-001 (ENST00000301067.11) - Summary - Homo sapiens - Ensembl genome browser 88" (in en-gb). http://www.ensembl.org/Homo_sapiens/Transcript/Summary?db=core;g=ENSG00000167548;r=12:49018975-49059774;t=ENST00000301067. 
  17. ↑ "The COMPASS family of H3K4 methylases in Drosophila". Molecular and Cellular Biology 31 (21): 4310–8. November 2011. doi:10.1128/MCB.06092-11. PMID 21875999. 
  18. ↑ "Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark". Molecular Cell 25 (1): 15–30. January 2007. doi:10.1016/j.molcel.2006.12.014. PMID 17218268. 
  19. ↑ 19.0 19.1 19.2 "H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability". Journal of Molecular Biology 429 (13): 2046–2054. December 2016. doi:10.1016/j.jmb.2016.12.016. PMID 28013028. 
  20. ↑ "Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation". Molecular Cell 66 (4): 568–576.e4. May 2017. doi:10.1016/j.molcel.2017.04.018. PMID 28483418. 
  21. ↑ "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. January 2003. doi:10.1128/mcb.23.1.140-149.2003. PMID 12482968. 
  22. ↑ 22.0 22.1 22.2 "PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex". The Journal of Biological Chemistry 282 (28): 20395–406. July 2007. doi:10.1074/jbc.M701574200. PMID 17500065. 
  23. ↑ "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. March 2007. doi:10.1128/MCB.01506-06. PMID 17178841. 
  24. ↑ "Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination". Science 318 (5849): 447–50. October 2007. doi:10.1126/science.1149042. PMID 17761849. Bibcode: 2007Sci...318..447L. 
  25. ↑ "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. November 2008. doi:10.1074/jbc.M806317200. PMID 18829457. 
  26. ↑ "WRAD: enabler of the SET1-family of H3K4 methyltransferases". Briefings in Functional Genomics 11 (3): 217–26. May 2012. doi:10.1093/bfgp/els017. PMID 22652693. 
  27. ↑ "Affi nity Purifi cation of MLL3/MLL4 Histone H3K4 Methyltransferase Complex". Transcriptional Regulation. Methods in Molecular Biology. 809. 2012. pp. 465–72. doi:10.1007/978-1-61779-376-9_30. ISBN 978-1-61779-375-2. 
  28. ↑ "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. November 2007. doi:10.1073/pnas.0707292104. PMID 18003914. Bibcode: 2007PNAS..10418439H. 
  29. ↑ 29.0 29.1 "MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis". Nucleic Acids Research 45 (11): 6388–6403. April 2017. doi:10.1093/nar/gkx234. PMID 28398509. 
  30. ↑ "KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation". Development 143 (5): 810–21. March 2016. doi:10.1242/dev.132688. PMID 26932671. 
  31. ↑ "KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation". Oncotarget 4 (11): 2144–53. November 2013. doi:10.18632/oncotarget.1555. PMID 24240169. 
  32. ↑ "UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells". Cancer Research 74 (6): 1705–17. March 2014. doi:10.1158/0008-5472.CAN-13-1896. PMID 24491801. 
  33. ↑ "Identification of the MLL2 complex as a coactivator for estrogen receptor alpha". The Journal of Biological Chemistry 281 (23): 15714–20. June 2006. doi:10.1074/jbc.M513245200. PMID 16603732. 
  34. ↑ "PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D". Science 355 (6331): 1324–1330. March 2017. doi:10.1126/science.aah6893. PMID 28336670. Bibcode: 2017Sci...355.1324T. 
  35. ↑ "How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum". European Journal of Human Genetics 20 (4): 381–388. April 2012. doi:10.1038/ejhg.2011.220. PMID 22126750. 
  36. ↑ "Unmasking Kabuki syndrome". Clinical Genetics 83 (3): 201–211. March 2013. doi:10.1111/cge.12051. PMID 23131014. 
  37. ↑ "A mutation screen in patients with Kabuki syndrome". Human Genetics 130 (6): 715–724. December 2011. doi:10.1007/s00439-011-1004-y. PMID 21607748. 
  38. ↑ "MLL2 mutation spectrum in 45 patients with Kabuki syndrome". Human Mutation 32 (2): E2018–E2025. February 2011. doi:10.1002/humu.21416. PMID 21280141. 
  39. ↑ "MLL2 mosaic mutations and intragenic deletion-duplications in patients with Kabuki syndrome". Clinical Genetics 83 (5): 467–471. May 2013. doi:10.1111/j.1399-0004.2012.01955.x. PMID 22901312. 
  40. ↑ "OMIM Entry - # 147920 - KABUKI SYNDROME 1; KABUK1". https://omim.org/entry/147920. 
  41. ↑ "Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2". Genetics in Medicine 23 (7): 1202–1210. July 2021. doi:10.1038/s41436-021-01119-8. PMID 33674768. 
  42. ↑ "De novo mutations in histone-modifying genes in congenital heart disease". Nature 498 (7453): 220–3. June 2013. doi:10.1038/nature12141. PMID 23665959. PMC 3706629. Bibcode: 2013Natur.498..220Z. https://dash.harvard.edu/bitstream/handle/1/11879354/3706629.pdf?sequence=1. 
  43. ↑ "Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations". Nature 488 (7409): 106–10. August 2012. doi:10.1038/nature11329. PMID 22820256. Bibcode: 2012Natur.488..106P. 
  44. ↑ "The genetic landscape of the childhood cancer medulloblastoma". Science 331 (6016): 435–9. January 2011. doi:10.1126/science.1198056. PMID 21163964. Bibcode: 2011Sci...331..435P. 
  45. ↑ "Dissecting the genomic complexity underlying medulloblastoma". Nature 488 (7409): 100–5. August 2012. doi:10.1038/nature11284. PMID 22832583. Bibcode: 2012Natur.488..100J. 
  46. ↑ "Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene". Genes, Chromosomes & Cancer 54 (9): 542–54. September 2015. doi:10.1002/gcc.22267. PMID 26032282. 
  47. ↑ "Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma". Nature 476 (7360): 298–303. July 2011. doi:10.1038/nature10351. PMID 21796119. Bibcode: 2011Natur.476..298M. 
  48. ↑ "The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome". Nature Genetics 47 (12): 1465–70. December 2015. doi:10.1038/ng.3442. PMID 26551667. 
  49. ↑ "Mutational landscape and significance across 12 major cancer types". Nature 502 (7471): 333–9. October 2013. doi:10.1038/nature12634. PMID 24132290. Bibcode: 2013Natur.502..333K. 
  50. ↑ "Genetic landscape of esophageal squamous cell carcinoma". Nature Genetics 46 (10): 1097–102. October 2014. doi:10.1038/ng.3076. PMID 25151357. 
  51. ↑ "Genomic and molecular characterization of esophageal squamous cell carcinoma". Nature Genetics 46 (5): 467–73. May 2014. doi:10.1038/ng.2935. PMID 24686850. 
  52. ↑ "Identification of genomic alterations in oesophageal squamous cell cancer". Nature 509 (7498): 91–5. May 2014. doi:10.1038/nature13176. PMID 24670651. Bibcode: 2014Natur.509...91S. 
  53. ↑ "Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients". Nature Communications 6: 7686. July 2015. doi:10.1038/ncomms8686. PMID 26154128. Bibcode: 2015NatCo...6.7686S. 
  54. ↑ "The mutational landscape of lethal castration-resistant prostate cancer". Nature 487 (7406): 239–43. July 2012. doi:10.1038/nature11125. PMID 22722839. Bibcode: 2012Natur.487..239G. 

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