Aberrant REST-mediated transcriptional regulation in major depressive disorder

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Abstract

There is growing evidence that aberrant transcriptional regulation is one of the key components of the pathophysiology of mood disorders. The repressor element-1 silencing transcription factor (REST) is a negative regulator of genes that contain the repressor element-1 (RE-1) binding site. REST has many target genes, including corticotropin releasing hormone (CRH), brain-derived neurotrophic factor, serotonin 1A receptor, which are suggested to be involved in the pathophysiology of depression and the action of antidepressants. However, a potential role for REST-mediated transcriptional regulation in mood disorders remains unclear. In this study, we examined the mRNA levels of REST and its known and putative target genes, using quantitative real-time PCR in peripheral blood cells of patients with major depressive and bipolar disorders in both a current depressive and a remissive state. We found reduced mRNA expression of REST and increased mRNA expression of CRH, adenylate cyclase 5, and the tumor necrosis factor superfamily, member 12–13 in patients with major depressive disorder in a current depressive state, but not in a remissive state. Altered expression of these mRNAs was not found in patients with bipolar disorder. Our results suggest that the aberrant REST-mediated transcriptional regulation of, at least, CRH, adenylate cyclase 5, and tumor necrosis factor superfamily, member 12–13, might be state-dependent and associated with the pathophysiology of major depression.

Introduction

While the pathophysiology of mood disorder is not completely understood, recent reports have focused on the long-term molecular changes that underlie mood disorders and treatment with antidepressants (Nestler et al., 2002, Duman et al., 2006). Aberrant regulation of gene expression represents a major component of mood disorders and the action of antidepressants (Nestler et al., 2002, Duman et al., 2006). The altered expression of a variety of transcription factors such as the glucocorticoid receptor and the cAMP-responsive element binding protein are associated with mood disorders and stressed animals (Holsboer, 2000, Nestler et al., 2002, Webster et al., 2002, Carlezon et al., 2005, de Kloet et al., 2005, Laifenfeld et al., 2005). In addition, antidepressants and/or mood stabilizers alter gene expression patterns in the brain (Manji et al., 1999, Coyle and Duman, 2003). Mood disorder patients and chronically stressed humans have also been reported to show alterations of gene expression in peripheral blood cells (Matsubara et al., 2006, Anitha et al., 2008, Miller et al., 2008, Otsuki et al., 2008).

Repressor element-1 silencing transcription factor (REST), also termed neuron-restrictive silencing factor, is a modular protein that contains, in addition to a DNA-binding domain with eight consecutive zinc fingers, two independent repression domains located at the N- and C-terminals of the molecule (Chong et al., 1995, Schoenherr and Anderson, 1995, Tapia-Ramirez et al., 1997). This zinc finger protein binds to a conserved consensus sequence called repressor element-1 (RE-1), also called the neuron-restrictive silencing element, allowing the transcriptional repression of RE-1 containing target genes, most of which are expressed in neurons (Chong et al., 1995, Schoenherr and Anderson, 1995, Tapia-Ramirez et al., 1997). In the central nervous system, it is believed that the REST – RE-1 system serves as a molecular switch that helps to distinguish neuronal from non-neuronal cell types, as the repression was thought to occur in non-neuronal cells, which contain REST, but not in neuronal cells, which either lack or contain only relatively low levels of REST (Kraner et al., 1992, Mori et al., 1992, Schoenherr and Anderson, 1995, Chong et al., 1995). Recent evidence suggests that REST and its target genes are involved in the regulation of neuronal terminal differentiation (Chong et al., 1995, Schoenherr et al., 1996), neurogenesis (Ballas et al., 2005, Westbrook et al., 2008) and synaptic plasticity (Schoenherr and Anderson, 1995). Although the dysregulation of REST and its target genes have been implicated in the pathogenesis of Down’s syndrome (Bahn et al., 2002), Alzheimer’s disease (Okazaki et al., 1995), Huntington’s disease (Zuccato et al., 2007) and ischemic insults (Calderone et al., 2003), its association with the pathophysiology of mood disorders remains unknown.

A recent report indicated that REST has many target genes including corticotropin releasing hormone (CRH), brain-derived neurotrophic factor, and the serotonin (5-HT) 1A receptor (Otto et al., 2007), which are suggested to be involved in mood disorders and/or the action of antidepressants in humans and rodents (Lemonde et al., 2003, Nestler et al., 2002, Duman et al., 2006). In addition, the repressive activity of REST is modulated by a recruitment of histone deacetylases, chromatin remodeling molecules, which are suggested to be involved in mood disorders and/or the action of antidepressants (Tsankova et al., 2006, Schroeder et al., 2007). Furthermore, depressed individuals often exhibit hypercortisolaemia (de Kloet et al., 2005), and a more recent study demonstrated that REST-mediated transcriptional regulation is involved in the synthesis of cortisol/corticosterone (Somekawa et al., 2009). These observations prompted us to postulate a role for aberrant REST-mediated gene regulation in the pathogenesis of mood disorders.

In this study, to investigate whether the mRNA expression of REST is altered in mood disorder patients, we assessed the mRNA levels of REST and a variety of its target genes, including CRH, 5-HT1A, adenylate cyclase 5 (Adcy5), calcium/calmodulin-dependent kinase II α (CaMKIIa), erythropoietin receptor (Epor), insulin-like growth factor 1 receptor (IGF1R), tumor necrosis factor superfamily, member 10 (Tnfsf10), Tnfsf11, and Tnfsf12–13 using quantitative real-time PCR in peripheral blood cells from major depressive and bipolar disorder patients. Furthermore, to examine whether the altered expression of these mRNAs is state- or trait-dependent, mRNA levels were examined in both current depressive and remissive states.

Section snippets

Subjects

Major depressive and bipolar disorder patients were diagnosed according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV; American Psychiatric Association, 1994). These included both outpatients and inpatients of the Division of Neuropsychiatry of the Yamaguchi University Hospital. The extent of the depressive state was assessed by a 21-item “Hamilton Depression Rating Scale” (HDRS). Subjects were classified as under a current depressive state

Results

Table 2 shows the demographic and clinical characteristics of the subjects. The majority of the patients were on medications. The mean ages were not significantly different among major depressive disorder patients, bipolar depressive patients and healthy control subjects (F = 1.263, df = 4,129, p = 0.288). Regarding the gender distribution, bipolar disorder patients showed a significantly larger ratio of females to males (χ2 = 19.565, p < 0.001). There was no significant association of gender with the

Discussion

In the present study, we found reduced mRNA expression of REST and increased mRNA expression of CRH, Adcy5, and Tnfsf12–13 in peripheral white blood cells of major depressive disorder patients in a current depressive state. In contrast, in a remissive state, the mRNA expression of REST, CRH, Adcy5 and Tnfsf12–13 in major depressive disorder patients were comparable to those of healthy controls. These results suggest that the reduced mRNA expression of REST and the increased mRNA expression of

Conflict of interest

There are no conflicts of interest including any financial, personal, or other relationships with people for any of the coauthors related to the work described in the article.

Contributors

K. Otsuki, S. Uchida and Y. Watanabe designated the research. K. Otsuki, Y. Wakabayashi, T. Matsubara, T. Hobara, and H. Funato performed the experiments. The manuscript was written by K. Otsuki, S. Uchida and Y. Watanabe. All authors discussed results and commented on the manuscript.

Role of funding sources

This study was supported in part by a Grant-in-Aid for Scientific Research from Japanese Ministry of Education, Culture, Sports, Science and Technology and a grant for Research on Psychiatric and Neurological Diseases and Mental Health from Japanese Ministry of Health, Labor and Welfare.

Acknowledgements

The authors thank Ms. Ayumi Kobayashi and Ms. Kumiko Hara for their excellent technical assistance.

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