EHMT2 explained

Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a histone methyltransferase enzyme that in humans is encoded by the EHMT2 gene.^{[1] [2] [3]} G9a deposits the mono- and di-methylated states of histone H3 at lysine residue 9 (i.e., H3K9me1 and H3K9me2) and lysine residue 27 (H3K27me1 and H3K27me2).^[4] The presence of H3K9me1/2 is usually associated with gene silencing.

Function

A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. This gene is found near this cluster; it was mapped near the gene for C2 within a 120-kb region that included a HSP70 gene pair. These genes are all within the human major histocompatibility complex class III region. This gene was thought to be two different genes, NG36 and G9a, adjacent to each other but a recent publication shows that there is only a single gene. The protein encoded by this gene is thought to be involved in intracellular protein-protein interaction. There are three alternatively spliced transcript variants of this gene but only two are fully described.^[3]

G9a and G9a-like protein, another histone-lysine N-methyltransferase, catalyze the synthesis of H3K9me2, which is a repressive mark.^{[5] [6]} G9a is an important control mechanism for epigenetic regulation within the nucleus accumbens (NAcc); reduced G9a expression in the NAcc plays a central role in mediating the development of an addiction. G9a opposes increases in ΔFosB expression via H3K9me2 and is suppressed by ΔFosB.^[7] G9a exerts opposite effects to that of ΔFosB on drug-related behavior (e.g., self-administration) and synaptic remodeling (e.g., dendritic arborization – the development of additional tree-like dendritic branches and spines) in the nucleus accumbens, and therefore opposes ΔFosB's function as well as increases in its expression.^[8] G9a and ΔFosB share many of the same gene targets.^[9] In addition to its role in the nucleus accumbens, G9a play a critical role in the development and the maintenance of neuropathic pain.^{[10] [11]} Following peripheral nerve injury, G9a regulates the expression of +600 genes in the dorsal root ganglia. This transcriptomic change reprograms the sensory neurons to a hyperexcitable state leading to mechanical pain hypersensitivity. ^[10]

Interactions

EHMT2 has been shown to interact with KIAA0515 and the prostate tissue associated homeodomain protein NKX3.1.^{[12] [13]}

EHMT2 in cancer

EHMT2 is known to drive process such as self-renewal and tumorigenicity, and its dysregulation can be associated with cancer. Abnormal EHMT2 expression is found both in haematological malignancies, as for example leukemia, and in solid tumors, as colorectal cancer, lung cancer, head and neck tumours.^[14]

Further reading

• Spies T, Bresnahan M, Strominger JL . Human major histocompatibility complex contains a minimum of 19 genes between the complement cluster and HLA-B . Proceedings of the National Academy of Sciences of the United States of America . 86 . 22 . 8955–8 . November 1989 . 2813433 . 298409 . 10.1073/pnas.86.22.8955 . 1989PNAS...86.8955S . free .
• Brown SE, Campbell RD, Sanderson CM . Novel NG36/G9a gene products encoded within the human and mouse MHC class III regions . Mammalian Genome . 12 . 12 . 916–24 . December 2001 . 11707778 . 10.1007/s00335-001-3029-3 . 9510386 .
• Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y . A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells . Science . 296 . 5570 . 1132–6 . May 2002 . 12004135 . 10.1126/science.1069861 . 2002Sci...296.1132O . 34863978 .
• Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H, Shinkai Y . G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis . Genes & Development . 16 . 14 . 1779–91 . July 2002 . 12130538 . 186403 . 10.1101/gad.989402 .
• Shi Y, Sawada J, Sui G, el Affar B, Whetstine JR, Lan F, Ogawa H, Luke MP, Nakatani Y, Shi Y . Coordinated histone modifications mediated by a CtBP co-repressor complex . Nature . 422 . 6933 . 735–8 . April 2003 . 12700765 . 10.1038/nature01550 . 2003Natur.422..735S . 2670859 .
• Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, Campbell RD, Hood L . Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse . Genome Research . 13 . 12 . 2621–36 . December 2003 . 14656967 . 403804 . 10.1101/gr.1736803 .
• Roopra A, Qazi R, Schoenike B, Daley TJ, Morrison JF . Localized domains of G9a-mediated histone methylation are required for silencing of neuronal genes . Molecular Cell . 14 . 6 . 727–38 . June 2004 . 15200951 . 10.1016/j.molcel.2004.05.026 . free .
• Nishio H, Walsh MJ . CCAAT displacement protein/cut homolog recruits G9a histone lysine methyltransferase to repress transcription . Proceedings of the National Academy of Sciences of the United States of America . 101 . 31 . 11257–62 . August 2004 . 15269344 . 509191 . 10.1073/pnas.0401343101 . 2004PNAS..10111257N . free .
• Collins RE, Tachibana M, Tamaru H, Smith KM, Jia D, Zhang X, Selker EU, Shinkai Y, Cheng X . In vitro and in vivo analyses of a Phe/Tyr switch controlling product specificity of histone lysine methyltransferases . The Journal of Biological Chemistry . 280 . 7 . 5563–70 . February 2005 . 15590646 . 2696276 . 10.1074/jbc.M410483200 . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Duan Z, Zarebski A, Montoya-Durango D, Grimes HL, Horwitz M . Gfi1 coordinates epigenetic repression of p21Cip/WAF1 by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1 . Molecular and Cellular Biology . 25 . 23 . 10338–51 . December 2005 . 16287849 . 1291230 . 10.1128/MCB.25.23.10338-10351.2005 .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . January 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 .
• Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP . A probability-based approach for high-throughput protein phosphorylation analysis and site localization . Nature Biotechnology . 24 . 10 . 1285–92 . October 2006 . 16964243 . 10.1038/nbt1240 . 14294292 .
• Reeves M, Murphy J, Greaves R, Fairley J, Brehm A, Sinclair J . Autorepression of the human cytomegalovirus major immediate-early promoter/enhancer at late times of infection is mediated by the recruitment of chromatin remodeling enzymes by IE86 . Journal of Virology . 80 . 20 . 9998–10009 . October 2006 . 17005678 . 1617317 . 10.1128/JVI.01297-06 .
• Estève PO, Chin HG, Smallwood A, Feehery GR, Gangisetty O, Karpf AR, Carey MF, Pradhan S . Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication . Genes & Development . 20 . 22 . 3089–103 . November 2006 . 17085482 . 1635145 . 10.1101/gad.1463706 .

Notes and References

1. Milner CM, Campbell RD . The G9a gene in the human major histocompatibility complex encodes a novel protein containing ankyrin-like repeats . The Biochemical Journal . 290 . Pt 3 . 811–8 . March 1993 . 8457211 . 1132354 . 10.1042/bj2900811 .
2. Tachibana M, Sugimoto K, Fukushima T, Shinkai Y . Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3 . The Journal of Biological Chemistry . 276 . 27 . 25309–17 . July 2001 . 11316813 . 10.1074/jbc.M101914200 . free .
3. Web site: Entrez Gene: EHMT2 euchromatic histone-lysine N-methyltransferase 2.
4. Book: Nestler EJ . Role of the Brain's Reward Circuitry in Depression: Transcriptional Mechanisms . International Review of Neurobiology . 124 . 151–70 . August 2015 . 26472529 . 4690450 . 10.1016/bs.irn.2015.07.003 . 9780128015834 .
5. Web site: Histone-lysine N-methyltransferase, H3 lysine-9 specific 3 . HIstome: The Histone Infobase . 8 June 2018 . 12 June 2018 . https://web.archive.org/web/20180612135816/http://www.actrec.gov.in/histome/enzyme_sp.php?enzyme_sp=Histone-lysine_N-methyltransferase,_H3_lysine-9_specific_3 . dead .
6. Web site: Histone-lysine N-methyltransferase, H3 lysine-9 specific 5 . HIstome: The Histone Infobase . 8 June 2018 . 12 June 2018 . https://web.archive.org/web/20180612140934/http://www.actrec.gov.in/histome/enzyme_sp.php?enzyme_sp=Histone-lysine_N-methyltransferase,_H3_lysine-9_specific_5 . dead .
7. Whalley K . Psychiatric disorders: a feat of epigenetic engineering . Nature Reviews. Neuroscience . 15 . 12 . 768–9 . December 2014 . 25409693 . 10.1038/nrn3869 . 11513288 . free .
8. Nestler EJ . Epigenetic mechanisms of drug addiction . Neuropharmacology . 76 . Pt B . 259–68 . January 2014 . 23643695 . 3766384 . 10.1016/j.neuropharm.2013.04.004 .
9. Robison AJ, Nestler EJ . Transcriptional and epigenetic mechanisms of addiction . Nature Reviews. Neuroscience . 12 . 11 . 623–37 . October 2011 . 21989194 . 3272277 . 10.1038/nrn3111 .
   Figure 4: Epigenetic basis of drug regulation of gene expression
10. Laumet . Geoffroy . G9a is essential for epigenetic silencing of K+ channel genes in acute-to-chronic pain transition . Nature Neuroscience . 18 . 12 . 1746–1755 . 10.1038/nn.4165 . 26551542. 4661086 . 2015 .
11. Liang . Lingli . G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons . Scientific Reports . 6 . 37704 . 10.1038/srep37704 . 27874088. 5118693 . 2016 . 2016NatSR...637704L .
12. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 . Huda Zoghbi .
13. Dutta A et al . Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation . Science . 352 . 6293 . 1576–80 . June 2016. 10.1126/science.aad9512 . 27339988 . 5507586 . 2016Sci...352.1576D .
14. Haebe . Joshua R. . Bergin . Christopher J. . Sandouka . Tamara . Benoit . Yannick D. . 2021-11-13 . Emerging role of G9a in cancer stemness and promises as a therapeutic target . Oncogenesis . 10 . 11 . 76 . 10.1038/s41389-021-00370-7 . 2157-9024 . 8590690 . 34775469.