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Review
.2009;11(3):257-68.
doi: 10.31887/DCNS.2009.11.3/wrenthal.

Chromatin regulation in drug addiction and depression

Affiliations
Review

Chromatin regulation in drug addiction and depression

William Renthal et al. Dialogues Clin Neurosci.2009.

Abstract
in English, Spanish, French

Alterations in gene expression are implicated in the pathogenesis of several neuropsychiatric disorders, including drug addiction and depression. Increasing evidence indicates that changes in gene expression in neurons, in the context of animal models of addiction and depression, are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular, and bioinformatic approaches that are being used to understand the complex epigenetic regulation of gene expression in brain by drugs of abuse and by stress. These advances promise to open up new avenues for improved treatments of these disorders.

Las alteraciones en la expresión génica están implicadas en la patogénesis de varios trastornos neuropsiquiátricos, incluyendo la adicción a drogas y la depresión. Existe una evidencia creciente que indica que los cambios en la expresión génica en las neuronas, en el contexto de modelos animales de adicción y depresión, están mediados en parte por mecanismos epigenéticos que alteran la estructura de la cromatina de genes promotores especificos. Esta revisión discute hallazgos recientes que provienen de aproximaciones conductuales, moleculares y bioinformáticas los cuales están siendo utilizados para comprender la compleja regulación epigenética de la expresión génica en el cerebro por las drogas de abuso y por el estrés. Estos avances prometen establecer nuevos caminos para mejores tratamientos de estos trastornos.

Des modifications de l'expression génique sont impliquées dans la pathogenèse de plusieurs maladies neuropsychiatriques, y compris la toxicomanie et la dépression. Des modèles animaux de ces pathologies montrent de plus en plus que des variations de l'expression des gènes dans les neurones sont transmises en partie par des mécanismes épigénétiques qui changent la structure de la chromatine sur les promoteurs spécifiques des gènes. Cet article analyse les résultats récents des approches comportementales, moléculaires et bioinformatiques utilisées pour comprendre la régulation épigénétique complexe de l'expression génique dans le cerveau par l'abus de substances et par le stress. Ces avancées ouvrent de nouvelles voies pour mieux traiter ces maladies.

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Figures

Figure 1.
Figure 1.. Chromatin remodeling. A. Picture of a nucleosome shoving a DNA strand wrapped around a histone octamer composed of two copies each of the histones H2A, H2B, H3 and H4. The amino (N) termini of the histones face outward from the nucleosome complex. B. Chromatin can be conceptualized as existing in two primary structural states; as active, or open, euchromatin (top left) in which histone acetylation (A) is associated with opening the nucleosome to alloy; binding of the basal transcriptional complex and other activators of transcription; or as inactive, or condensed, heterochromatin where all gene activity is permanently silenced (bottom left). In reality, chromatin exists in a continuum of functional states in between (eg, active; permissive (top right); repressed (bottom right); and inactive). Enrichment of histone modifications such as acetylation and methylation (M) at histone N-terminal tails and related binding of transcription factors and coactivators (Co-Act) or repressors (Rep) to chromatin modulates the transcriptional state of the nucleosome. Recent evidence suggests that inactivated chromatin may in some cases be subject to reactivation in adult nerve cells, although this remains uncertain. C. Summary of common covalent modifications of H3, which include acetylation, methylation, and phosphorylation (P) at several amino acid residues. H3 phosphoacetylation commonly involves phosphorylation of S10 and acetylation of K14. Acetylation of lysine residues is catalysed by histone acetyltransferases (HATs) and reversed by histone deacetylases (HDACs); lysine methylation (which can be either activating or repressing) is catalyzed by histone methyltransferases (HMTs) and reversed by histone demethylases (HDMs); and phosphorylation is catalysed by protein kinases (PK) and reversed by protein phosphatases (PP), which have not yet been identified with certainty. K, lysine residue; S, serine residue. From ref 8: Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders.Nat Rev Neurosci. 2007;8:355-367.
Figure 2.
Figure 2.. Regulation of chromatin structure by drugs of abuse. Drug-induced signaling events are depicted for psychostimulants such as cocaine and amphetamine. These drugs increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes includingfosB andc-fos in response to psychostimulant exposure. AFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg,cdk5) and repress others (eg,c-fos) where it recruits HDAC1 as a corepressor. This repression ofc-fos also involves increased repressive histone methylation, which is thought to occur via the induction of specific histone methyltransferases (HMTs). In addition, cocaine regulates the HMT, KMT1 C/G9a, which alters histone H3 methylation on K9. It is not yet known how cocaine regulates histone demethylases (HDM) or DNA methyltransferases (DNMTs). Cocaine also activates the mitogen activated protein kinase (MAPK) cascade, which through MSK1 can phosphorylate CREB and histone H3 at serine 10. Cocaine promotes H3 phosphorylation via a distinct pathway, whereby PKA activates protein phosphatase 2A, leading to the dephosphorylation of serine 97 of DARPP32. This causes DARPP32 to accumulate in the nucleus and inhibit protein phosphatase-1 (PP1) which normally dephosphorylates H3. Chronic exposure to psychostimulants increases glutamatergic stignaling from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5. This results in nuclear export of HDAC5 and increased histone acetylation on its target genes (eg, NK1R[NK1 or substance P receptor]). From ref 8: Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders.Nat Rev Neurosci. 2007;8:355-367.
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