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].

Function

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EHMT1(Euchromatic histone-lysine N-methyltransferase 1) is a gene which produces an enzyme, EHMT1. This enzyme modifies DNA to give it heterochromatic features[2]. This form of regulation is known as epigenetic regulation because the modification does not directly interact with the DNA strand itself[2]. The protein encoded by this gene is a histone methyltransferase that is part of the E2F6 complex, which represses transcription. The encoded protein mono or  dimethylates the Lys-9 position of histone H3, which tags it for transcriptional repression. This protein may be involved in the transcriptional silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition[1]. The EHMT1 pathway is still relatively unknown, although new information and studies are currently underway and ongoing.

Associated Genes, Proteins and other Factors

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EHMT1's main interaction is at the Lysine 9 position of the histone tail of H3[3]. EHMT1 has also been shown to interact in a network through genetic interactions[4]. This network was established through studies in protein knockouts in drosophila orthologs[4]. The genes shown to have genetic interaction with EHMT1 were MBD5, MLL3 and NR113. NR113 and MBD5 were shown to have a synergystic relationship with EHMT1, while MLL3's interaction was suggested to be antagonistic[4]. EHMT1 has also been shown to interact with nuclear factors such as the kB p50 factor during methylation of histonetail, these recruited molecules then repress transcription[5]. The genes that EHMT1 are involved with in silencing involve the MYC and E2F- responsive genes, these genes are known to have roles in the transition between G0 and G1 cell cycle[1].

Intellectual Disability and EHMT1

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Kleefstra Syndrome or 9q subtelomeric deletion syndrome is a form of intellectual disability and in 25% of the cases EHMT1 has a mutation that causes the phenotype[4].  Kleefstra syndrome can develop from haploinsufficiency of the EMT1 gene, for this reason Kleefstra syndrome arises through de Novo mutations or else the phenotype would have been seen in the parental phenotype (except in rare X-linked maternal cases)[6][4]. Mutations not only to the exome of the EHMT1 gene have been shown to produce the Kleefstra phenotype but mutations in the 5’ UTR have also been shown to produce the phenotype, this realization has been taken into account by researchers by searching and sequencing the entire EHMT1 transcribed region and not just the exons[7].

Future/Current Studies

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The future and current studies involving EHMT1 involve finding more proteins and other cellular processes and pathways that interact or affect EHMT1.  This area of study is being investigated further because of all the patients who have shown the Kleefstra phenotype, only approximately 25% of them have been shown to have mutations directly affecting EHMT1[4].  The investigation now turns to its associated genes, proteins and RNA’s that may genetically or physically interact with with EHMT1. The goal of these studies is to try to discover the entire pathway(s) that EHMT1 is associated with. So that in the future patients with disorders such as Kleefstra Syndrome can be diagnosed on a patient to patient basis and can be treated on a patient to patient basis. Being that 25% of Kleefstra Syndrome patients have an EHMT1 mutation, there are another 75% of patients that would need different methods of treatment to best help those who suffer from intellectual disability resulting from mutations to genes, proteins, and RNA's that interact with EHMT1 in some fashion.

References

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  1. ^ a b c "EHMT1 euchromatic histone-lysine N-methyltransferase 1 [Homo sapiens (human)]". NCBI. 2012. {{cite journal}}: |access-date= requires |url= (help)
  2. ^ a b Kramer, Jamie (2008). "Genetic and Epigenetic defects in mental retardation". The International Journal of Biochemistry and Cell Biology.
  3. ^ Akbarian, S (2008). "Epigenetic Regulation in Human Brain—Focus on Histon Lysine Methylation". Biological Phychiatry. {{cite journal}}: line feed character in |title= at position 47 (help)
  4. ^ a b c d e f Kleefstra, T (2012). "Disruption of an EHMT1-Associted Chromatin- Modification Module Causes Intellectual Disability". Journal of Human Genetics.
  5. ^ Chee-Kwee, Ea (2012). "EHMT1 Protein Binds to Nuclear Factor-􏰀B p50 and Represses Gene Expression". Journal of Biological Chemistry. {{cite journal}}: line feed character in |title= at position 59 (help)
  6. ^ Kleefstra, T (2006). "Loss-of-Function Mutation in Euchromatin Histone Methyl Transferase 1 (EHMT1) Cause the 9q34 Subtelomeric Deletion Syndrome". Journal of Human Genetics.
  7. ^ Nillesen, W (2011). "Characterization of a novel transcript of the EHMT1 gene reveals important diagnostic implications for Kleefstra syndrome". Human Mutation. {{cite journal}}: line feed character in |title= at position 58 (help)