Biology:EHMT1

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Short description: Protein-coding gene in the species Homo sapiens


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

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.[3][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.[5] 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.[3] Therefore, it is thought that G9A cannot compensate for the loss of GLP methyltransferase activity in vivo, and vice versa.[3] 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.[3] 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][3] 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.[3][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][9][11][12] For example, G9A/GLP can methylate a number of transcription factors to regulate their transcriptional activity, including MyoD,[13] C/EBP,[12] Reptin,[11] 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,[16][13] establishing and maintaining cell identity,[13][20] cell cycle regulation,[14] and cellular responses to environmental stimuli,[11]  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 Keefstra syndrome-1).[1]

Dysregulation of EHMT1 has been implicated in inflammatory and cardiovascular diseases.[21][22][23][24]

References

  1. ↑ 1.0 1.1 "Entrez Gene: Euchromatic histone-lysine N-methyltransferase 1". https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=79813. 
  2. ↑ "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. doi:10.1086/505693. PMID 16826528. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "H3K9 methyltransferase G9a and the related molecule GLP". Genes & Development 25 (8): 781–8. April 2011. doi:10.1101/gad.2027411. PMID 21498567. 
  4. ↑ "Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase". Journal of Medicinal Chemistry 60 (5): 1876–1891. March 2017. doi:10.1021/acs.jmedchem.6b01645. PMID 28135087. 
  5. ↑ 5.0 5.1 "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. doi:10.1101/gad.1284005. PMID 15774718. 
  6. ↑ "G9a/GLP Complex Maintains Imprinted DNA Methylation in Embryonic Stem Cells". Cell Reports 15 (1): 77–85. April 2016. doi:10.1016/j.celrep.2016.03.007. PMID 27052169. 
  7. ↑ "Epigenetic control". Journal of Cellular Physiology 219 (2): 243–50. May 2009. doi:10.1002/jcp.21678. PMID 19127539. 
  8. ↑ "Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease". Genes & Development 22 (9): 1115–40. May 2008. doi:10.1101/gad.1652908. PMID 18451103. 
  9. ↑ 9.0 9.1 "Non-histone protein methylation as a regulator of cellular signalling and function". Nature Reviews. Molecular Cell Biology 16 (1): 5–17. January 2015. doi:10.1038/nrm3915. PMID 25491103. http://www.nature.com/articles/nrm3915. 
  10. ↑ "Novel Function of Lysine Methyltransferase G9a in the Regulation of Sox2 Protein Stability". PLOS ONE 10 (10): e0141118. 2015-10-22. doi:10.1371/journal.pone.0141118. PMID 26492085. Bibcode: 2015PLoSO..1041118L. 
  11. ↑ 11.0 11.1 11.2 "Negative regulation of hypoxic responses via induced Reptin methylation". Molecular Cell 39 (1): 71–85. July 2010. doi:10.1016/j.molcel.2010.06.008. PMID 20603076. 
  12. ↑ 12.0 12.1 "G9a-mediated lysine methylation alters the function of CCAAT/enhancer-binding protein-beta". The Journal of Biological Chemistry 283 (39): 26357–63. September 2008. doi:10.1074/jbc.M802132200. PMID 18647749. 
  13. ↑ 13.0 13.1 13.2 "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. doi:10.1073/pnas.1111628109. PMID 22215600. Bibcode: 2012PNAS..109..841L. 
  14. ↑ 14.0 14.1 "G9a and Glp methylate lysine 373 in the tumor suppressor p53". The Journal of Biological Chemistry 285 (13): 9636–41. March 2010. doi:10.1074/jbc.M109.062588. PMID 20118233. 
  15. ↑ "Modulation of lysine methylation in myocyte enhancer factor 2 during skeletal muscle cell differentiation". Nucleic Acids Research 42 (1): 224–34. January 2014. doi:10.1093/nar/gkt873. PMID 24078251. 
  16. ↑ 16.0 16.1 "G9a inhibits MEF2C activity to control sarcomere assembly". Scientific Reports 6 (1): 34163. September 2016. doi:10.1038/srep34163. PMID 27667720. Bibcode: 2016NatSR...634163O. 
  17. ↑ "A core chromatin remodeling factor instructs global chromatin signaling through multivalent reading of nucleosome codes". Molecular Cell 49 (4): 704–18. February 2013. doi:10.1016/j.molcel.2012.12.016. PMID 23352453. 
  18. ↑ "MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a". Nature Communications 2: 533. November 2011. doi:10.1038/ncomms1549. PMID 22086334. Bibcode: 2011NatCo...2..533C. 
  19. ↑ "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. doi:10.1073/pnas.1014660108. PMID 21427230. Bibcode: 2011PNAS..108.5718L. 
  20. ↑ "Recruitment of coregulator G9a by Runx2 for selective enhancement or suppression of transcription". Journal of Cellular Biochemistry 113 (7): 2406–14. July 2012. doi:10.1002/jcb.24114. PMID 22389001. 
  21. ↑ "The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy". The Journal of Clinical Investigation 127 (1): 335–348. January 2017. doi:10.1172/JCI88353. PMID 27893464. 
  22. ↑ "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. doi:10.1161/ATVBAHA.119.312765. PMID 31434493. 
  23. ↑ "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. doi:10.1038/ni.1968. PMID 21131967. 
  24. ↑ "The role of smooth muscle cells in plaque stability: Therapeutic targeting potential". British Journal of Pharmacology 176 (19): 3741–3753. October 2019. doi:10.1111/bph.14779. PMID 31254285. 

External links

  • Overview of all the structural information available in the PDB for UniProt: Q9H9B1 (Histone-lysine N-methyltransferase EHMT1) at the PDBe-KB.



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