EHMT1 explained

Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a protein that in humans is encoded by the EHMT1 gene.[1]

Structure

EHMT1 messenger RNA is alternatively spliced to produce three predicted protein isoforms. Starting from the N-terminus, the canonical isoform one has eight ankyrin repeats, a pre-SET, and a SET domains. Isoforms two and three have missing or incomplete C-terminal SET domains respectively.[2]

Function

G9A-like protein (GLP) shares an evolutionary conserved SET domain with G9A, responsible for methyltransferase activity.[3] The SET domain primarily functions to establish and maintain H3K9 mono and di-methylation, a marker of faculative heterochromatin.[4] When transiently over expressed, G9A and GLP form homo- and heterodimers via their SET domain.[5] However, endogenously both enzymes function exclusively as a heteromeric complex. Although G9A and GLP can exert their methyltransferase activities independently in vitro, if either G9a or Glp are knocked out in vivo, global levels of H3K9me2 are severely reduced and are equivalent to H3K9me2 levels in G9a and Glp double knockout mice. Therefore, it is thought that G9A cannot compensate for the loss of GLP methyltransferase activity in vivo, and vice versa. Another important functional domain, which G9A and GLP both share, is a region containing ankryin repeats, which is involved in protein-protein interactions. The ankyrin repeat domain also contains H3K9me1 and H3K9me2 binding sites. Therefore, the G9A/GLP complex can both methylate histone tails and bind to mono- and di-methylated H3K9 to recruit molecules, such as DNA methyltransferases, to the chromatin.[6] H3K9me2 is a reversible modification and can be removed by a wide range of histone lysine demethylases (KDMs) including KDM1, KDM3, KDM4 and KDM7 family members.[7] [8]

In addition to their role as histone lysine methyltransferases (HMTs), several studies have shown that G9A/GLP are also able to methylate a wide range of non-histone proteins.[9] However, as most of the reported methylation sites have been derived from mass spectrometry analyses, the function of many of these modifications remain unknown. Nevertheless, increasing evidence suggests methylation of non-histone proteins may influence protein stability, protein-protein interactions and regulate cellular signalling pathways.[10] [11] [12] For example, G9A/GLP can methylate a number of transcription factors to regulate their transcriptional activity, including MyoD,[13] C/EBP, Reptin, p53,[14] MEF2D,[15] MEF2C[16] and MTA1.[17] Furthermore, G9A/GLP are able to methylate non-histone proteins to regulate complexes which recruit DNA methyltransferases to gene promoters to repress transcription via the methylation of CpG islands.[18] [19] Therefore, G9A and/or GLP have wide-ranging roles in development, establishing and maintaining cell identity,[20] cell cycle regulation, and cellular responses to environmental stimuli,  which are dependent on their non-histone protein methyltransferase activity.

Clinical significance

Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome or Kleefstra syndrome-1).[21]

Dysregulation of EHMT1 has been implicated in inflammatory and cardiovascular diseases.[22] [23] [24] [25]

Notes and References

  1. Web site: Entrez Gene: Euchromatic histone-lysine N-methyltransferase 1. 2012-03-04 .
  2. Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Magee A, Geneviève D, Cormier-Daire V, van Esch H, Fryns JP, Hamel BC, Sistermans EA, de Vries BB, van Bokhoven H . 6 . Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome . American Journal of Human Genetics . 79 . 2 . 370–7 . August 2006 . 16826528 . 1559478 . 10.1086/505693 .
  3. Shinkai Y, Tachibana M . H3K9 methyltransferase G9a and the related molecule GLP . Genes & Development . 25 . 8 . 781–8 . April 2011 . 21498567 . 3078703 . 10.1101/gad.2027411 .
  4. Xiong Y, Li F, Babault N, Dong A, Zeng H, Wu H, Chen X, Arrowsmith CH, Brown PJ, Liu J, Vedadi M, Jin J . 6 . Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase . Journal of Medicinal Chemistry . 60 . 5 . 1876–1891 . March 2017 . 28135087 . 5352984 . 10.1021/acs.jmedchem.6b01645 .
  5. Tachibana M, Ueda J, Fukuda M, Takeda N, Ohta T, Iwanari H, Sakihama T, Kodama T, Hamakubo T, Shinkai Y . 6 . Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9 . Genes & Development . 19 . 7 . 815–26 . April 2005 . 15774718 . 1074319 . 10.1101/gad.1284005 .
  6. Zhang T, Termanis A, Özkan B, Bao XX, Culley J, de Lima Alves F, Rappsilber J, Ramsahoye B, Stancheva I . 6 . G9a/GLP Complex Maintains Imprinted DNA Methylation in Embryonic Stem Cells . Cell Reports . 15 . 1 . 77–85 . April 2016 . 27052169 . 4826439 . 10.1016/j.celrep.2016.03.007 .
  7. Delcuve GP, Rastegar M, Davie JR . Epigenetic control . Journal of Cellular Physiology . 219 . 2 . 243–50 . May 2009 . 19127539 . 10.1002/jcp.21678 . 39355478 .
  8. Cloos PA, Christensen J, Agger K, Helin K . Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease . Genes & Development . 22 . 9 . 1115–40 . May 2008 . 18451103 . 2732404 . 10.1101/gad.1652908 .
  9. Biggar KK, Li SS . Non-histone protein methylation as a regulator of cellular signalling and function . Nature Reviews. Molecular Cell Biology . 16 . 1 . 5–17 . January 2015 . 25491103 . 10.1038/nrm3915 . 12558106 .
  10. Lee JY, Lee SH, Heo SH, Kim KS, Kim C, Kim DK, Ko JJ, Park KS . 6 . Novel Function of Lysine Methyltransferase G9a in the Regulation of Sox2 Protein Stability . PLOS ONE . 10 . 10 . e0141118 . 2015-10-22 . 26492085 . 10.1371/journal.pone.0141118 . 4619656 . 2015PLoSO..1041118L . free .
  11. Lee JS, Kim Y, Kim IS, Kim B, Choi HJ, Lee JM, Shin HJ, Kim JH, Kim JY, Seo SB, Lee H, Binda O, Gozani O, Semenza GL, Kim M, Kim KI, Hwang D, Baek SH . 6 . Negative regulation of hypoxic responses via induced Reptin methylation . Molecular Cell . 39 . 1 . 71–85 . July 2010 . 20603076 . 4651011 . 10.1016/j.molcel.2010.06.008 .
  12. Pless O, Kowenz-Leutz E, Knoblich M, Lausen J, Beyermann M, Walsh MJ, Leutz A . G9a-mediated lysine methylation alters the function of CCAAT/enhancer-binding protein-beta . The Journal of Biological Chemistry . 283 . 39 . 26357–63 . September 2008 . 18647749 . 3258912 . 10.1074/jbc.M802132200 . free .
  13. Ling BM, Bharathy N, Chung TK, Kok WK, Li S, Tan YH, Rao VK, Gopinadhan S, Sartorelli V, Walsh MJ, Taneja R . 6 . Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation . Proceedings of the National Academy of Sciences of the United States of America . 109 . 3 . 841–6 . January 2012 . 22215600 . 3271886 . 10.1073/pnas.1111628109 . 2012PNAS..109..841L . free .
  14. Huang J, Dorsey J, Chuikov S, Pérez-Burgos L, Zhang X, Jenuwein T, Reinberg D, Berger SL . 6 . G9a and Glp methylate lysine 373 in the tumor suppressor p53 . The Journal of Biological Chemistry . 285 . 13 . 9636–41 . March 2010 . 20118233 . 2843213 . 10.1074/jbc.M109.062588 . free .
  15. Choi J, Jang H, Kim H, Lee JH, Kim ST, Cho EJ, Youn HD . Modulation of lysine methylation in myocyte enhancer factor 2 during skeletal muscle cell differentiation . Nucleic Acids Research . 42 . 1 . 224–34 . January 2014 . 24078251 . 3874188 . 10.1093/nar/gkt873 .
  16. Ow JR, Palanichamy Kala M, Rao VK, Choi MH, Bharathy N, Taneja R . G9a inhibits MEF2C activity to control sarcomere assembly . Scientific Reports . 6 . 1 . 34163 . September 2016 . 27667720 . 5036183 . 10.1038/srep34163 . 2016NatSR...634163O .
  17. Nair SS, Li DQ, Kumar R . A core chromatin remodeling factor instructs global chromatin signaling through multivalent reading of nucleosome codes . Molecular Cell . 49 . 4 . 704–18 . February 2013 . 23352453 . 3582764 . 10.1016/j.molcel.2012.12.016 .
  18. Chang Y, Sun L, Kokura K, Horton JR, Fukuda M, Espejo A, Izumi V, Koomen JM, Bedford MT, Zhang X, Shinkai Y, Fang J, Cheng X . 6 . MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a . Nature Communications . 2 . 533 . November 2011 . 22086334 . 3286832 . 10.1038/ncomms1549 . 2011NatCo...2..533C .
  19. Leung DC, Dong KB, Maksakova IA, Goyal P, Appanah R, Lee S, Tachibana M, Shinkai Y, Lehnertz B, Mager DL, Rossi F, Lorincz MC . 6 . Lysine methyltransferase G9a is required for de novo DNA methylation and the establishment, but not the maintenance, of proviral silencing . Proceedings of the National Academy of Sciences of the United States of America . 108 . 14 . 5718–23 . April 2011 . 21427230 . 3078371 . 10.1073/pnas.1014660108 . 2011PNAS..108.5718L . free .
  20. Purcell DJ, Khalid O, Ou CY, Little GH, Frenkel B, Baniwal SK, Stallcup MR . Recruitment of coregulator G9a by Runx2 for selective enhancement or suppression of transcription . Journal of Cellular Biochemistry . 113 . 7 . 2406–14 . July 2012 . 22389001 . 3350606 . 10.1002/jcb.24114 .
  21. Web site: Entrez Gene: Euchromatic histone-lysine N-methyltransferase 1. 2012-03-04 .
  22. Thienpont B, Aronsen JM, Robinson EL, Okkenhaug H, Loche E, Ferrini A, Brien P, Alkass K, Tomasso A, Agrawal A, Bergmann O, Sjaastad I, Reik W, Roderick HL . 6 . The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy . The Journal of Clinical Investigation . 127 . 1 . 335–348 . January 2017 . 27893464 . 5199699 . 10.1172/JCI88353 .
  23. Harman JL, Dobnikar L, Chappell J, Stokell BG, Dalby A, Foote K, Finigan A, Freire-Pritchett P, Taylor AL, Worssam MD, Madsen RR, Loche E, Uryga A, Bennett MR, Jørgensen HF . 6 . Epigenetic Regulation of Vascular Smooth Muscle Cells by Histone H3 Lysine 9 Dimethylation Attenuates Target Gene-Induction by Inflammatory Signaling . Arteriosclerosis, Thrombosis, and Vascular Biology . 39 . 11 . 2289–2302 . November 2019 . 31434493 . 6818986 . 10.1161/ATVBAHA.119.312765 .
  24. Levy D, Kuo AJ, Chang Y, Schaefer U, Kitson C, Cheung P, Espejo A, Zee BM, Liu CL, Tangsombatvisit S, Tennen RI, Kuo AY, Tanjing S, Cheung R, Chua KF, Utz PJ, Shi X, Prinjha RK, Lee K, Garcia BA, Bedford MT, Tarakhovsky A, Cheng X, Gozani O . 6 . Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling . Nature Immunology . 12 . 1 . 29–36 . January 2011 . 21131967 . 3074206 . 10.1038/ni.1968 .
  25. Harman JL, Jørgensen HF . The role of smooth muscle cells in plaque stability: Therapeutic targeting potential . British Journal of Pharmacology . 176 . 19 . 3741–3753 . October 2019 . 31254285 . 6780045 . 10.1111/bph.14779 .

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