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{{Infobox_gene}}
{{Infobox_gene}}
'''Euchromatic histone-lysine N-methyltransferase 2''' (EHMT2), also known as '''G9a''', is a [[histone methyltransferase]] that in humans is encoded by the ''EHMT2'' [[gene]].<ref name="pmid8457211">{{cite journal | vauthors = Milner CM, Campbell RD | title = The G9a gene in the human major histocompatibility complex encodes a novel protein containing ankyrin-like repeats | journal = The Biochemical Journal | volume = 290 | issue = Pt 3 | pages = 811–8 | date = Mar 1993 | pmid = 8457211 | pmc = 1132354 | doi = 10.1042/bj2900811}}</ref><ref name="pmid11316813">{{cite journal | vauthors = Tachibana M, Sugimoto K, Fukushima T, Shinkai Y | title = 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 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 27 | pages = 25309–17 | date = Jul 2001 | pmid = 11316813 | pmc = | doi = 10.1074/jbc.M101914200 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: EHMT2 euchromatic histone-lysine N-methyltransferase 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10919| accessdate = }}</ref> G9a catalyzes the dimethylation of H3K9 (i.e., [[histone H3]] at [[lysine]] residue 9), which is a [[Histone#Chromatin regulation|repressive histone modification]].<ref name="pmid26472529">{{cite journal | vauthors = Nestler EJ | title = Role of the Brain's Reward Circuitry in Depression: Transcriptional Mechanisms | journal = Int. Rev. Neurobiol. | volume = 124 | issue = | pages = 151–170 | date = August 2015 | pmid = 26472529 | pmc = 4690450 | doi = 10.1016/bs.irn.2015.07.003 | quote = Chronic social defeat stress decreases expression of G9a and GLP (G9a-like protein), two histone methyltransferases that catalyze the dimethylation of Lys9 of histone H3 (H3K9me2) (Covington et al., 2011), a mark associated with gene repression.}}</ref>
'''Euchromatic histone-lysine N-methyltransferase 2''' (EHMT2), also known as '''G9a''', is a [[histone methyltransferase]] that in humans is encoded by the ''EHMT2'' [[gene]].<ref name="pmid8457211">{{cite journal | vauthors = Milner CM, Campbell RD | title = The G9a gene in the human major histocompatibility complex encodes a novel protein containing ankyrin-like repeats | journal = The Biochemical Journal | volume = 290 | issue = Pt 3 | pages = 811–8 | date = Mar 1993 | pmid = 8457211 | pmc = 1132354 | doi = 10.1042/bj2900811}}</ref><ref name="pmid11316813">{{cite journal | vauthors = Tachibana M, Sugimoto K, Fukushima T, Shinkai Y | title = 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 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 27 | pages = 25309–17 | date = Jul 2001 | pmid = 11316813 | pmc = | doi = 10.1074/jbc.M101914200 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: EHMT2 euchromatic histone-lysine N-methyltransferase 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10919| accessdate = }}</ref> G9a catalyzes the mono- and di-methylated states of [[histone H3]] at [[lysine]] residue 9 (i.e., [[H3K9me1]] and [[H3K9me2]]) and lysine residue 27 ([[H3K27me1]] and [[HeK27me2]]).<ref name="pmid26472529">{{cite journal | vauthors = Nestler EJ | title = Role of the Brain's Reward Circuitry in Depression: Transcriptional Mechanisms | journal = Int. Rev. Neurobiol. | volume = 124 | issue = | pages = 151–170 | date = August 2015 | pmid = 26472529 | pmc = 4690450 | doi = 10.1016/bs.irn.2015.07.003 | quote = Chronic social defeat stress decreases expression of G9a and GLP (G9a-like protein), two histone methyltransferases that catalyze the dimethylation of Lys9 of histone H3 (H3K9me2) (Covington et al., 2011), a mark associated with gene repression.}}</ref>


== Function ==
== Function ==
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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.<ref name="entrez"/>
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.<ref name="entrez"/>


G9a and [[G9a-like protein]], another histone-lysine N-methyltransferase, catalyze the mono- and di-methylated states of [[histone H3]] at lysine residue 9 (i.e., [[H3K9me1]] and [[H3K9me2]]) and lysine residue 27 ([[H3K27me1]] and [[HeK27me2]]).<ref name="pmid26472529" /><ref name="Histome G9a">{{cite web |title=Histone-lysine N-methyltransferase, H3 lysine-9 specific 3 |url=http://www.actrec.gov.in/histome/enzyme_sp.php?enzyme_sp=Histone-lysine_N-methyltransferase,_H3_lysine-9_specific_3 |publisher=HIstome: The Histone Infobase |accessdate=8 June 2018|quote=}}</ref><ref name="Histome GLP">{{cite web |title=Histone-lysine N-methyltransferase, H3 lysine-9 specific 5 |url=http://www.actrec.gov.in/histome/enzyme_sp.php?enzyme_sp=Histone-lysine_N-methyltransferase,_H3_lysine-9_specific_5 |publisher=HIstome: The Histone Infobase |accessdate=8 June 2018}}</ref> G9a is an important control mechanism for [[epigenetic regulation]] within the [[nucleus accumbens]], particularly during the development of an addiction, since G9a opposes the induction of [[ΔFosB]] expression and is suppressed by ΔFosB.<ref name="Nestler 2014 epigenetics" /> 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 [[dendrite|dendritic branches]] and [[dendritic spine|spines]]) in the nucleus accumbens, and therefore opposes ΔFosB's function as well as increases in its expression.<ref name="Nestler 2014 epigenetics">{{cite journal | vauthors = Nestler EJ | title = Epigenetic mechanisms of drug addiction | journal = Neuropharmacology | volume = 76 Pt B | issue = | pages = 259–268 | date = January 2014 | pmid = 23643695 | pmc = 3766384 | doi = 10.1016/j.neuropharm.2013.04.004 | quote = Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine’s effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors.&nbsp;... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).<br />G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a).&nbsp;... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine’s behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. }}</ref> G9a and ΔFosB share many of the same gene targets.<ref name="Nestler1">{{cite journal | author = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | volume = 12 | issue = 11 | pages = 623–637 | date = November 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote = ΔFosB serves as one of the master control proteins governing this structural plasticity.&nbsp;... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression.&nbsp;... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1).&nbsp;... The net result is c-fos gene repression.&nbsp;... G9a and ΔFosB share many of the same target genes.}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277/figure/F4/ Figure 4: Epigenetic basis of drug regulation of gene expression]</ref>
G9a and [[G9a-like protein]], another histone-lysine N-methyltransferase, catalyze the synthesis of [[H3K9me2]], which is a [[repressor|repressive]] mark.<ref name="pmid26472529" /><ref name="Histome G9a">{{cite web |title=Histone-lysine N-methyltransferase, H3 lysine-9 specific 3 |url=http://www.actrec.gov.in/histome/enzyme_sp.php?enzyme_sp=Histone-lysine_N-methyltransferase,_H3_lysine-9_specific_3 |publisher=HIstome: The Histone Infobase |accessdate=8 June 2018|quote=}}</ref><ref name="Histome GLP">{{cite web |title=Histone-lysine N-methyltransferase, H3 lysine-9 specific 5 |url=http://www.actrec.gov.in/histome/enzyme_sp.php?enzyme_sp=Histone-lysine_N-methyltransferase,_H3_lysine-9_specific_5 |publisher=HIstome: The Histone Infobase |accessdate=8 June 2018}}</ref> G9a is an important control mechanism for [[epigenetic regulation]] within the [[nucleus accumbens]], particularly during the development of an addiction, since G9a opposes increases in [[ΔFosB]] expression via [[H3K9me2]] and is suppressed by ΔFosB.<ref name="Nestler 2014 epigenetics" /> 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 [[dendrite|dendritic branches]] and [[dendritic spine|spines]]) in the nucleus accumbens, and therefore opposes ΔFosB's function as well as increases in its expression.<ref name="Nestler 2014 epigenetics">{{cite journal | vauthors = Nestler EJ | title = Epigenetic mechanisms of drug addiction | journal = Neuropharmacology | volume = 76 Pt B | issue = | pages = 259–268 | date = January 2014 | pmid = 23643695 | pmc = 3766384 | doi = 10.1016/j.neuropharm.2013.04.004 | quote = Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine’s effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors.&nbsp;... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).<br />G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a).&nbsp;... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine’s behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. }}</ref> G9a and ΔFosB share many of the same gene targets.<ref name="Nestler1">{{cite journal | author = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | volume = 12 | issue = 11 | pages = 623–637 | date = November 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote = ΔFosB serves as one of the master control proteins governing this structural plasticity.&nbsp;... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression.&nbsp;... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1).&nbsp;... The net result is c-fos gene repression.&nbsp;... G9a and ΔFosB share many of the same target genes.}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277/figure/F4/ Figure 4: Epigenetic basis of drug regulation of gene expression]</ref>


== Interactions ==
== Interactions ==

Revision as of 09:44, 8 June 2018

EHMT2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesEHMT2, BAT8, C6orf30, G9A, GAT8, KMT1C, NG36, euchromatic histone lysine methyltransferase 2
External IDsOMIM: 604599; MGI: 2148922; HomoloGene: 48460; GeneCards: EHMT2; OMA:EHMT2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10919

110147

Ensembl

ENSMUSG00000013787

UniProt

Q96KQ7

Q9Z148

RefSeq (mRNA)

NM_001286573
NM_001286575
NM_145830
NM_147151

RefSeq (protein)

NP_001276342
NP_001305762
NP_006700
NP_079532
NP_001350618

Location (UCSC)Chr 6: 31.88 – 31.9 MbChr 17: 35.12 – 35.13 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a histone methyltransferase that in humans is encoded by the EHMT2 gene.[5][6][7] G9a catalyzes the mono- and di-methylated states of histone H3 at lysine residue 9 (i.e., H3K9me1 and H3K9me2) and lysine residue 27 (H3K27me1 and HeK27me2).[8]

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.[7]

G9a and G9a-like protein, another histone-lysine N-methyltransferase, catalyze the synthesis of H3K9me2, which is a repressive mark.[8][9][10] G9a is an important control mechanism for epigenetic regulation within the nucleus accumbens, particularly during the development of an addiction, since G9a opposes increases in ΔFosB expression via H3K9me2 and is suppressed by ΔFosB.[11] 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.[11] G9a and ΔFosB share many of the same gene targets.[12]

Interactions

EHMT2 has been shown to interact with KIAA0515 and the prostate tissue associated homeodomain protein NKX3.1.[13][14]

References

  1. ^ a b c ENSG00000224143, ENSG00000206376, ENSG00000204371, ENSG00000227333, ENSG00000232045, ENSG00000236759 GRCh38: Ensembl release 89: ENSG00000238134, ENSG00000224143, ENSG00000206376, ENSG00000204371, ENSG00000227333, ENSG00000232045, ENSG00000236759 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000013787 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Milner CM, Campbell RD (Mar 1993). "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. doi:10.1042/bj2900811. PMC 1132354. PMID 8457211.
  6. ^ Tachibana M, Sugimoto K, Fukushima T, Shinkai Y (Jul 2001). "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. doi:10.1074/jbc.M101914200. PMID 11316813.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ a b "Entrez Gene: EHMT2 euchromatic histone-lysine N-methyltransferase 2".
  8. ^ a b Nestler EJ (August 2015). "Role of the Brain's Reward Circuitry in Depression: Transcriptional Mechanisms". Int. Rev. Neurobiol. 124: 151–170. doi:10.1016/bs.irn.2015.07.003. PMC 4690450. PMID 26472529. Chronic social defeat stress decreases expression of G9a and GLP (G9a-like protein), two histone methyltransferases that catalyze the dimethylation of Lys9 of histone H3 (H3K9me2) (Covington et al., 2011), a mark associated with gene repression.
  9. ^ "Histone-lysine N-methyltransferase, H3 lysine-9 specific 3". HIstome: The Histone Infobase. Retrieved 8 June 2018.
  10. ^ "Histone-lysine N-methyltransferase, H3 lysine-9 specific 5". HIstome: The Histone Infobase. Retrieved 8 June 2018.
  11. ^ a b Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).
    G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation.
  12. ^ Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression. ... G9a and ΔFosB share many of the same target genes.
    Figure 4: Epigenetic basis of drug regulation of gene expression
  13. ^ 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 (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
  14. ^ Dutta A, et al. (Jun 2016). "Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation". Science.

Further reading

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