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Social Isolation Stress Induces ATF-7 Phosphorylation and Impairs Silencing of the 5-HT 5B Receptor Gene

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Social Isolation Stress Induces ATF-7 Phosphorylation and Impairs Silencing of the 5-HT 5B Receptor Gene The EMBO Journal (2010) 29, 184–195 | & 2010 European Molecular Biology Organization | All Rights Reserved 0261-4189/10 www.embojournal.org TTHEH E EEMBOMBO JJOURNALOURN AL Social isolation stress induces ATF-7 phosphorylation and impairs silencing of the 5-HT 5B receptor gene Toshio Maekawa1,6,*, Seungjoon Kim1,6,7, Introduction Daisuke Nakai1,2, Chieko Makino1,2,8, 1 3 ATF-7 (originally called ATFa) is structurally related to ATF-2 Tsuyoshi Takagi , Hiroo Ogura , (Hai et al, 1989; Maekawa et al, 1989; Gaire et al, 1990), Kazuyuki Yamada4, Bruno Chatton5 1,2, a member of the ATF–CREB family of transcription factors. and Shunsuke Ishii * ATF-2, ATF-7, and CRE-BPa (Nomura et al, 1993) form a 1Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, subfamily in the ATF–CREB family. Each of these three Tsukuba, Ibaraki, Japan, 2University of Tsukuba, Graduate School of factors contains a transcription-activation domain consisting 3 Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan, Tsukuba of a metal-finger structure and stress-activated protein kinase Research Laboratories, Eisai Co., Ltd, Ibaraki, Japan, 4Support Unit for Animal Experiment, Research Resources Center, Brain Science (SAPK) phosphorylation sites, and a b-ZIP type DNA-binding Institute (BSI), RIKEN, Wako, Saitama, Japan and 5Ecole Supe´rieure domain. Various stresses, including inflammatory cytokines, de Biotechnologie de Strasbourg, Universite´ Louis Pasteur, Parc activate SAPKs such as p38 and JNK (Davis, 2000), which d’innovation, UMR7100 CNRS-ULP, Strasbourg, Illkirch Cedex, France then phosphorylate ATF-2 and activate its trans-activating capacity (Gupta et al, 1995; Livingstone et al, 1997; van Dam Many symptoms induced by isolation rearing of rodents et al, 1997). ATF-7 is also phosphorylated by p38, but not by may be relevant to neuropsychiatric disorders, including JNK (De Graeve et al, 1999). ATF-2 and ATF-7 can form depression. However, identities of transcription factors homodimers or heterodimers with Jun and bind to cAMP that regulate gene expression in response to chronic social response element (CRE) (50-TGACGTCA-30) (Chatton et al, isolation stress remain elusive. The transcription factor 1994). ATF-7 is structurally related to ATF-2, which is activated ATF-7 binds to mouse ATFa-associated modulator (mAM) by various stresses, including inflammatory cytokines. which is a component of the ESET complex (De Graeve et al, Here, we report that Atf-7-deficient mice exhibit abnormal 2000; Wang et al, 2003). As ESET is a histone methyltransfer- behaviours and increased 5-HT receptor 5B (Htr5b) mRNA ase (HMTase) that converts lysine 9 of histone H3 (H3-K9) levels in the dorsal raphe nuclei. ATF-7 silences the from the dimethyl to the trimethyl form, therefore ATF-7 is 0 transcription of Htr5B by directly binding to its 5 -regula- thought to support gene silencing by inducing histone H3-K9 tory region, and mediates histone H3-K9 trimethylation trimethylation. Two reports have suggested a role for ATF-2 via interaction with the ESET histone methyltransferase. family transcription factors in epigenetic gene silencing. The Isolation-reared wild-type (WT) mice exhibit abnormal yeast homologue of ATF-2, Atf1, contributes to heterochro- behaviours that resemble those of Atf-7-deficient mice. matin formation independently of the RNAi machinery (Jia Upon social isolation stress, ATF-7 in the dorsal raphe et al, 2004). Vertebrate ATF-2 also interacts with the histone nucleus is phosphorylated via p38 and is released from variant macroH2A, which is enriched in the inactive X the Htr5b promoter, leading to the upregulation of Htr5b. chromosome in female mammalian cells and functions to Thus, ATF-7 may have a critical role in gene expression maintain gene silencing (Agelopoulos and Thanos, 2006). induced by social isolation stress. Both ATF-7 and ATF-2 are ubiquitously expressed in The EMBO Journal (2010) 29, 184–195. doi:10.1038/ various tissues, including the brain (Takeda et al, 1991; emboj.2009.318; Published online 5 November 2009 Goetz et al, 1996). Atf-2 null mice die immediately after Subject Categories: chromatin & transcription; neuroscience birth because of defects in respiration, which appear to be Keywords: 5-HT receptor; ATF-7; histone methylation; social caused by impaired proliferation of cytotrophoblasts in the isolation stress placenta (Maekawa et al, 1999). Atf-2 heterozygotes are highly prone to mammary tumours in which the expression levels of Maspin, a tumour suppressor, and Gadd45a, which is induced by hypoxic stress, are decreased (Maekawa et al, 2007). Both these genes encode the regulators of apoptosis, *Corresponding authors. T Maekawa or S Ishii, Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305- suggesting that defects in the apoptotic machinery are linked 0074, Japan. Tel.: þ 81 29 836 9031; Fax: þ 81 29 836 9030; to the occurrence of mammary tumours. In contrast, the E-mail: [email protected] or [email protected] physiological role of ATF-7 is unknown, although the Atf-2 6 These authors contributed equally to this work and Atf-7 double mutant exhibits embryonic lethality with 7Present address: Laboratory of Veterinary Reproduction, Kyungpook National University, Sankyuk-dong, Buk-gu Daegu 702-701, South Korea abnormalities in the developing liver and heart (Breitwieser 8Present address: Division of Molecular Genetics, Department of et al, 2007). Physiology and Cell Biology, Kobe University Graduate School of Human neuropsychiatric disorders, such as depression, Medicine, Kobe 650-0017, Japan have multiple-risk factors, including environmental and ge- Received: 12 December 2008; accepted: 8 October 2009; published netic factors. A loss of social contact is one environmental online: 5 November 2009 factor that appears to be linked to both the onset and relapse 184 The EMBO Journal VOL 29 | NO 1 | 2010 &2010 European Molecular Biology Organization ATF-7 and social isolation stress T Maekawa et al of depression (Paykel et al, 1980). Long-term social isolation of rodents after weaning provides a model to study the behavioural consequences of loss of social interactions. Many of the symptoms induced by isolation rearing may be relevant to neuropsychiatric disorders (Rodgers and Cole, 1993). Isolated animals are aggressive and exhibit anxiety- like behaviours and increased locomotor activity (Rodgers and Cole, 1993; Blanchard et al, 2001). One of the typical abnormal behaviour in isolation-reared mice is a deficit in pre-pulse inhibition (PPI) of the acoustic startle response (Wilkinson et al, 1994). In fact, isolation-induced disruption of PPI has been used as a disease model in screening antipsychotic drugs. In animal studies, isolation stress changes the activity of brain neurotransmitters (Blanc et al, 1980; Blanchard et al, 2001). In the case of acute stress, several transcription factors, including c-Fos and corticoster- oid receptors, are activated and modulate multiple target genes (Kaufer et al, 1998). However, the transcription factors that are activated and the regulation of gene expression patterns in response to a chronic stress, such as social isolation stress, remain elusive. In addition, as the effect of social isolation stress on behaviour is long-lived, this stress may cause epigenetic changes. However, the mechanism by which epigenetic change is caused by isolation stress remains unknown. In this study, we have demonstrated that Atf-7-deficient (Atf-7À/À) mice exhibit abnormal behaviours reminiscent of isolation-reared wild-type (WT) mice. Social isolation stress induced the phosphorylation of ATF-7 and p38 in the dorsal raphe nuclei, as well as a release of ATF-7 from the promoter of the 5-HT receptor 5B (Htr5b) gene, leading to an impaired silencing of this gene. Results Abnormal behaviours of Atf-7À/À mice We generated Atf-7À/À mice (Supplementary Figure S1), and, under pathogen-free conditions, Atf-7À/À mice appeared healthy until at least 12 months of age. As Atf-7 mRNA is expressed at relatively high levels in parts of the brain (Goetz et al, 1996), we examined various behaviours originally Atf-7À/À using WT and littermate mice with a mixed CBA À/À (25%) Â C57BL/6 (75%) genetic background, and later Figure 1 Abnormal behaviours in Atf-7 mice. Wild-type (WT; þ / þ ) and Atf-7À/À C57BL/6 congenic mice were used for all using C57BL/6 congenic mice. In the marble-burying test, assays. Data are mean±s.e.m. (A) Marble-burying test. **Po0.01 which is used to examine anxiety-related behaviours (n ¼ 10–12 for each group). (B) Center of the open-field test. Time (Spooren et al, 2000), Atf-7À/À mice exhibited increased spent in the center of the test apparatus is expressed as a percent of marble-burying behaviour compared with WT mice total time (10 min). NS, no significant difference (n ¼ 13–16 for each group). (C) Elevated plus-maze test. Mice were observed in an (Figure 1A and Supplementary Figure S2A). In other tests elevated plus-maze for 5 min. Percentage of entries into open arms of anxiety-related behaviours, such as the amount of time (left) and the time spent in open arms (right) are shown (n ¼ 13–16 spent in the centre of an open-field and the elevated plus- for each group). (D) Acoustic startle response. Amplitude of the maze test (Spooren et al, 2000), there was no significant startle response to a 120 dB acoustic stimulus is shown (n ¼ 13–16 À/À for each group). (E) Pre-pulse inhibition of the acoustic startle difference between Atf-7 and WT mice (Figure 1B and C response. The response to a white noise stimulus of 120 dB after a À/À and Supplementary Figure S2B). Atf-7 mice did exhibit a 20 ms pre-pulse warning stimulus (70 or 80 dB) is shown (n ¼ 13–16 significant increase in the startle response to a pulse-alone for each group).
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