EHMT2

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L'EHMT2 [( in inglese Euchromatic istone-lisina N-metiltransferasi 2, noto anche come G9a, è un istone metiltransferasi che nell'uomo è codificato dal gene EHMT2.[1][2][3]

Funzione[modifica | modifica wikitesto]

Un cluster di geni, BAT1-BAT5, è stato localizzato in prossimità dei geni per il fattore di necrosi tumorale noto anche come TNF α e β. La proteina codificata da questo gene si pensa possa essere coinvolta nelle interazioni intracellulari proteina-proteina . Ci sono tre varianti di trascrizione alternative di questo gene, ma solo due sono completamente note.[3]

Il G9a e l'EHMT1, un altro istone-lisina N-metiltransferasi, catalizza la dimetilizzazione di H3K9me2. G9a è un meccanismo di controllo importante per la regolazione epigenetica nel nucleus accumbens, in particolare durante lo sviluppo di una dipendenza, poiché G9a si oppone all'induzione dell'espressione ΔFosB ed è soppresso dal ΔFosB.[4] G9a esercita effetti opposti a quello di ΔFosB sui comportamenti legati all'assunzione di droga (come nell'auto-somministrazione) e il rimodellamento sinaptico (ad esempio, l'arborizzazione dendritica) nel nucleus accumbens, e si oppone quindi all'ΔFosB come aumentare la sua espressione.[4]

Note[modifica | modifica wikitesto]

  1. ^ Milner CM, Campbell RD, The G9a gene in the human major histocompatibility complex encodes a novel protein containing ankyrin-like repeats, in The Biochemical Journal, vol. 290, Pt 3, Mar 1993, pp. 811–8, PMC 1132354, PMID 8457211.
  2. ^ Tachibana M, Sugimoto K, Fukushima T, Shinkai Y, 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, in The Journal of Biological Chemistry, vol. 276, nº 27, Jul 2001, pp. 25309–17, DOI:10.1074/jbc.M101914200, PMID 11316813.
  3. ^ a b Entrez Gene: EHMT2 euchromatic histone-lysine N-methyltransferase 2, su ncbi.nlm.nih.gov.
  4. ^ a b Nestler EJ, Epigenetic mechanisms of drug addiction, in Neuropharmacology, 76 Pt B, January 2014, pp. 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.»
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