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Fosb Mediates Epigenetic Desensitization of the C-Fosgene

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Fosb Mediates Epigenetic Desensitization of the C-Fosgene 7344 • The Journal of Neuroscience, July 16, 2008 • 28(29):7344–7349 Brief Communications ⌬FosB Mediates Epigenetic Desensitization of the c-fos Gene After Chronic Amphetamine Exposure William Renthal,1 Tiffany L. Carle,1 Ian Maze,1 Herbert E. Covington III,1 Hoang-Trang Truong,1 Imran Alibhai,1 Arvind Kumar,1 Rusty L. Montgomery,2 Eric N. Olson,2 and Eric J. Nestler1 Departments of 1Psychiatry and Neuroscience and 2Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070 The molecular mechanisms underlying the transition from recreational drug use to chronic addiction remain poorly understood. One molecule implicated in this process is ⌬FosB, a transcription factor that accumulates in striatum after repeated drug exposure and mediatessensitizedbehavioralresponsestopsychostimulantsandotherdrugsofabuse.Thedownstreamtranscriptionalmechanismsby which ⌬FosB regulates drug-induced behaviors are incompletely understood. We reported previously the chromatin remodeling mech- anisms by which ⌬FosB activates the expression of certain genes; however, the mechanisms underlying ⌬FosB-mediated gene repression remain unknown. Here, we identify c-fos, an immediate early gene rapidly induced in striatum after acute psychostimulant exposure, as a novel downstream target that is repressed chronically by ⌬FosB. We show that accumulation of ⌬FosB in striatum after chronic amphetamine treatment desensitizes c-fos mRNA induction to a subsequent drug dose. ⌬FosB desensitizes c-fos expression by recruiting histone deacetylase 1 (HDAC1) to the c-fos gene promoter, which, in turn, deacetylates surrounding histones and attenuates gene activity. Accordingly, local knock-out of HDAC1 in striatum abolishes amphetamine-induced desensitization of the c-fos gene. In concert, chronic amphetamine increases histone H3 methylation on the c-fos promoter, a chromatin modification also known to repress gene activity, as well as expression levels of the H3 histone methyltransferase, KMT1A (lysine methyltransferase 1A, formerly SUV39H1). This study reveals a novel epigenetic pathway through which ⌬FosB mediates distinct transcriptional programs that may ultimately alter behavioral plasticity to chronic amphetamine exposure. Key words: addiction; amphetamine; striatum; chromatin; histone modification; gene regulation Introduction ⌬FosB in striatum provided the first insight into potential down- Repeated use of psychostimulants such as amphetamine and co- stream targets (McClung and Nestler, 2003). This study sug- caine often results in a transition from recreational drug use to a gested that ⌬FosB can serve as a transcriptional activator or re- chronically addicted state (Hyman et al., 2006). One mechanism pressor, depending on the target gene. However, the study implicated in this process involves the transcription factor examined transcripts regulated in an overexpression setting, so it ⌬FosB, a highly stable splice product of the immediate early gene is not clear which of these genes are direct, physiological ⌬FosB fosB, which dimerizes with Jun family proteins to form functional targets. AP-1 transcriptional complexes (McClung et al., 2004). ⌬FosB We recently identified the cyclin-dependent kinase 5 (cdk5) accumulates several-fold in striatum after repeated exposure to gene as a direct target for endogenous ⌬FosB, which promotes drugs of abuse, and this accumulation has been linked to in- Cdk5 transcription in striatum (Kumar et al., 2005). However, creased cocaine reward, locomotor sensitization, and self- the mechanisms involved in the repression of target genes by administration (Kelz et al., 1999; Colby et al., 2003; McClung et ⌬FosB have remained elusive. One attractive candidate is c-fos,a al., 2004), which together suggest a role in the neural mechanisms gene that is induced dramatically by acute psychostimulants but involved in transitioning between recreational and addicted drug only weakly after repeated exposure (Hope et al., 1992; Persico et use. According to this hypothesis, ⌬FosB functions in a positive al., 1993; Steiner and Gerfen, 1993), when levels of ⌬FosB and feedback loop by increasing drug-seeking behaviors, which, in ⌬FosB-containing AP-1 complexes are high (Hope et al., 1992, ⌬ turn, induce more FosB. One key outstanding question is how 1994). Because the c-fos gene contains an AP-1-like site in its ⌬ does FosB mediate its effects on drug-related behaviors? proximal promoter (Morgan and Curran, 1989), it is a plausible Genome-wide microarray studies in mice that overexpress candidate for ⌬FosB-mediated repression. Induction of c-fos is traditionally viewed as an early marker of neural activation be- Received March 10, 2008; revised April 29, 2008; accepted June 4, 2008. cause it is rapidly and transiently induced in response to a variety This work was supported by grants from the National Institute on Drug Abuse. of stimuli (Morgan and Curran, 1989). The c-fos gene is also CorrespondenceshouldbeaddressedtoEricJ.Nestler,DepartmentsofPsychiatryandNeuroscience,TheUniver- important for behavioral responses to cocaine, because mice sity of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070. E-mail: lacking c-fos in dopamine D1 receptor-containing neurons, the [email protected]. ⌬ DOI:10.1523/JNEUROSCI.1043-08.2008 neuronal cell type where FosB is induced by psychostimulants Copyright © 2008 Society for Neuroscience 0270-6474/08/287344-06$15.00/0 (McClung et al., 2004), have reduced behavioral sensitization to Renthal et al. • Epigenetic Desensitization of c-fos by Amphetamine J. Neurosci., July 16, 2008 • 28(29):7344–7349 • 7345 cocaine (Zhang et al., 2006). These findings led us to investigate uated for up to5dofdrug withdrawal (Fig. 1A), a point at which whether ⌬FosB controls c-fos gene activity after chronic amphet- ⌬FosB remains elevated in this brain region (Hope et al., 1994). amine exposure. We describe here a novel epigenetic mechanism Additionally, in rats that were withdrawn from chronic amphet- by which ⌬FosB accumulation in response to chronic amphet- amine for 5 d, we found that basal c-fos mRNA expression was amine feeds back to desensitize c-fos induction to subsequent reduced below levels found in saline-treated controls (Fig. 1A). drug doses. This novel interplay between ⌬FosB and chromatin Importantly, the magnitude of c-fos induction to an amphet- remodeling events on the c-fos promoter may be an important amine challenge was significantly attenuated at day 1 of with- homeostatic mechanism to regulate an animal’s sensitivity to re- drawal compared with saline-treated animals. Together, these peated drug exposure. findings demonstrate an effect of chronic amphetamine on both basal and induced c-fos mRNA levels, although with the two ef- Materials and Methods fects occurring with a complex time course. RNA isolation and quantification. Frozen brain tissue was thawed in To determine whether ⌬FosB accumulation after chronic am- TRIzol (Invitrogen) and processed according to the manufacturer’s pro- phetamine directly contributes to the desensitization of c-fos ex- tocol. RNA was purified with RNeasy Micro columns (Qiagen). Total pression, we first performed chromatin immunoprecipitation RNA was reverse-transcribed using Superscript III (Invitrogen). Real- (ChIP) for ⌬FosB on the c-fos gene promoter in striatum. As time PCR was then run using SYBR Green (ABI) and quantified using the shown in Figure 1B, the c-fos promoter has significantly more ⌬⌬Ct method. For a complete list of primers, see supplemental Table 1 ⌬FosB bound after chronic amphetamine exposure, an effect (available at www.jneurosci.org as supplemental material). seen for at least5dofdrug withdrawal. These data correlate Chromatin immunoprecipitation. Chromatin was sonicated and then ⌬ immunoprecipitated (supplemental Methods, available at www. FosB occupancy on the c-fos promoter with the kinetics of re- jneurosci.org as supplemental material) using acetylated histone anti- duced c-fos gene activity. Next, to directly test whether ⌬FosB bodies (Millipore), anti-histone deacetylase 1 (HDAC1) or anti-histone causes reduced c-fos induction in response to amphetamine chal- H3 dimethylated at lysine 9 (H3K9me2) (Abcam), anti-FosB (C termi- lenge, we used an AAV vector to overexpress either ⌬FosB, or nus) (Kumar et al., 2005), anti-FosB (N terminus) (Santa Cruz Biotech- GFP as a control, in the striatum. We then isolated the infected nology), or a rabbit IgG control (Millipore). The immunoprecipitation striatum by laser microdissection (Fig. 1C) and performed quan- was collected using Protein A beads from Millipore. After washing, chro- titative reverse transcription (qRT)-PCR for c-fos mRNA. We matin was eluted from the beads and reverse cross-linked in the presence observed significantly less c-fos mRNA induced after an acute of proteinase K. DNA was then purified and quantified using real-time dose of amphetamine in the striatal tissue infected with AAV- PCR. ⌬FosB compared with the contralateral side infected with AAV- Immunoprecipitation. PC12 cells were transfected with V5-tagged ␤ HDAC1 (Montgomery et al., 2007), FosB, or ⌬FosB as described previ- GFP, whereas levels of -tubulin mRNA remained unchanged ously (Carle et al., 2007). Cell lysates were split and incubated with either (Fig. 1D). These data suggest that c-fos desensitization is medi- nonimmune IgG (Sigma) or anti-FosB antibodies (sc-48; Santa Cruz ated by accumulation of ⌬FosB on its promoter after chronic Biotechnology)
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