H3K9me2

H3K9me2 is a covalent histone modification – specifically, the dimethylated state of histone H3 at lysine residue 9 – and an epigenetic mark that is strongly associated with transcriptional repression.[1][2][3] H3K9me2 synthesis is catalyzed by G9a, G9a-like protein, and PRDM2.[1][3][4] The repeat-rich regions of constitutive heterochromatin are enriched by dimethylation and trimethylation of histone 3 lysine 9 (H3K9me2 and H3K9me3).[5]

Nomenclature

H3K9me2 refers to the di-methylated state of lysine residue 9 on histone H3:

Abbr. Meaning
H3 H3 family of histones
K standard abbreviation for lysine
9 position of amino acid residue
(counting from N-terminus)
me methyl group
2 number of methyl groups added

Clinical significance

Addiction

References

  1. 1 2 "H3K9me2". HIstome: The Histone Infobase. Retrieved 8 June 2018.
  2. 1 2 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. ... Histone methylation is directly regulated by drugs of abuse as well: global levels of histone 3 lysine 9 dimethylation (H3K9me2) are reduced in the NAc after chronic cocaine37 and a genome-wide screen revealed alterations in H3K9me2 binding on the promoters of numerous genes in this brain region32; both increases and decreases were observed, indicating again that epigenetic modifications at individual genes often defy global changes. The global decrease in H3K9me2 in the NAc is likely mediated by cocaine-induced downregulation of two HMTs, G9a and G9a-like protein (GLP), which catalyze H3K9me237. These adaptations mediate enhanced responsiveness to cocaine, as selective knockout or pharmacological inhibition of G9a in the NAc promotes cocaine-induced behaviors, whereas G9a overexpression has the opposite effect. G9a likewise mediates the ability of cocaine to increase the spine density of NAc MSNs37 (Box 2). Interestingly, there is a functional feedback loop between G9a and ΔFosB: ΔFosB seems to be responsible for cocaine-induced suppression of G9a, and G9a binds to and represses the fosb promoter, such that G9a downregulation may promote the accumulation of ΔFosB observed after chronic cocaine37. In addition, G9a and ΔFosB share many of the same target genes. ... The mechanisms underlying such gene desensitization and priming remain incompletely understood; our hypothesis is that epigenetic mechanisms are crucial (Figure 3B). A subset of primed genes show reduced binding of G9a and H3K9me2 at their promoters in the NAc, suggesting the involvement of this epigenetic mark37. Desensitization of the c-fos gene in the NAc, discussed above and depicted in Figure 4, involves stable increases in the binding of ΔFosB, G9a, and related co-repressors, which—although not affecting steady-state levels of c-Fos mRNA—dramatically repress its inducibility to subsequent drug exposure91.
    Figure 4: Epigenetic basis of drug regulation of gene expression
  3. 1 2 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.
  4. ↑ "Histone-lysine N-methyltransferase, H3 lysine-9 specific 3". HIstome: The Histone Infobase. Retrieved 8 June 2018.
  5. ↑ Nakayama, Jun-ichi (2001). "Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly". Science. 292 (5514): 110–113. PMID 11283354.
  6. ↑ 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.
  7. ↑ Whalley K (December 2014). "Psychiatric disorders: a feat of epigenetic engineering". Nature Reviews. Neuroscience. 15 (12): 768–9. doi:10.1038/nrn3869. PMID 25409693. The authors showed that expression of constructs that promote transcriptional activation (Fosb-ZFP‑p65 and Fosb-TALE‑VP64) in the mouse NAc increased levels of Fosb as well as the level of H3K9 acetylation (an activating histone modification) at the Fosb promoter. Conversely, expression of a construct containing a transcriptionally repressive domain (Fosb-ZFP‑G9a) decreased Fosb expression and increased the level of the repressive histone modification H3K9me2. Thus, the engineered transcription factors induced specific histone modifications and regulated Fosb expression in vivo.
    Cocaine exposure induces Fosb expression in the NAc, and the authors showed that expression of Fosb-ZFP‑G9a blocked this induction. Furthermore, Fosb-ZFP‑G9a expression blocked the cocaine-induced enrichment of phosphorylated CREB at the Fosb promoter. H3K9me2 therefore regulates cocaine-induced Fosb expression by inhibiting transcription factor binding. ... Susceptibility to depression has been linked to reduced FOSB levels in humans and animal models. The authors showed here that expression of Fosb-ZFP‑G9a increased depression-like behaviour in a chronic social defeat stress model, indicating that the H3K9me2 modification mediates this effect.
    This study shows that single epigenetic modifications can modulate both Fosb expression and its behavioural effects.
  8. ↑ Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–496. PMID 23020045. For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... Methylation of histones is a vital consideration in the cocaine-induced remodelling of chromatin. Chronic cocaine treatment reduces the dimethylation of lysine 9 on histone H3, (H3K9me2) in the Accumbens nucleus (through suppressing the G9a gene coding for histone-dimethyltransferase), which modifies the expression of many other genes. Cocaine also induces high ΔFosB levels which inhibits the histone-dimethyltransferase, thus, in addition reducing the H3 dimethylation. ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
  9. ↑ Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, et al. (April 2013). "Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation". Nat. Neurosci. 16 (4): 434–440. doi:10.1038/nn.3354. PMC 3609040. PMID 23475113. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression. The same complexity has been reported previously with local knockdown of HDAC5 in the NAc16. ... The interaction between cocaine and MS-275 reported here is noteworthy. Either cocaine or MS-275 treatment alone caused global increases in H3 acetylation and increases in GABAA subunit gene expression, but when combined, these treatments caused increases in global repressive H3K9me2, most likely driven by a loss of HDAC1 and a subsequent gain in H3ac at H3K9 KMT promoters, that prevented cocaine-induced increases in GABAA subunit gene expression and inhibitory tone in NAc (Supplementary Fig. 5).
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