Epigenetics of Stress-Related Psychiatric Disorders and Gene 3 Environment Interactions
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Neuron Review Epigenetics of Stress-Related Psychiatric Disorders and Gene 3 Environment Interactions Torsten Klengel1,2 and Elisabeth B. Binder1,2,* 1Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany 2Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2015.05.036 A deeper understanding of the pathomechanisms leading to stress-related psychiatric disorders is important for the development of more efficient preventive and therapeutic strategies. Epidemiological studies indicate a combined contribution of genetic and environmental factors in the risk for disease. The environment, particularly early life severe stress or trauma, can lead to lifelong molecular changes in the form of epigenetic modifications that can set the organism off on trajectories to health or disease. Epigenetic modifications are capable of shaping and storing the molecular response of a cell to its environment as a function of genetic predisposition. This provides a potential mechanism for gene-environment interactions. Here, we review epigenetic mechanisms associated with the response to stress and trauma exposure and the development of stress-related psychiatric disorders. We also look at how they may contribute to our understanding of the combined effects of genetic and environmental factors in shaping disease risk. Introduction twin and family studies (Lee et al., 2013). This is likely accounted Psychiatric disorders and in particular stress-related psychiatric for by weak phenotype definitions potentially leading to a dilution disorders such as post-traumatic stress disorder (PTSD), major of genetic effects. Current diagnostic classification includes a depressive disorder (MDD), and anxiety disorders are multifacto- number of pathophysiological subtypes under the broad defini- rial diseases influenced by both genetic predisposition and envi- tions of anxiety and depressive disorders. In addition, genetic ronmental factors (Stein et al., 2002; Sullivan et al., 2000). factors may have considerably smaller effect sizes compared Adverse life events, especially early in life, have consistently to schizophrenia where the explained variance by polygenic been shown to strongly increase the risk for mood and anxiety factors has consistently increased with growing sample sizes disorders in large epidemiological studies (Kessler et al., 1997). (Schizophrenia Working Group of the Psychiatric Genomics Although severe forms of early adverse life events such as child- Consortium, 2014). In MDD, anxiety disorders, and PTSD, the hood abuse or neglect have been associated with the highest reliable detection of such polygenic risk factors may need rates of increased risk (Dube et al., 2001), other forms of early much larger samples (Levinson et al., 2014). adverse experiences, such as parental loss, bullying, or low so- Environmental factors as major triggers of stress-related dis- cioeconomic status in childhood, were also shown to consis- orders may lead to additional heterogeneity that is unaccounted tently increase risk for a number of psychiatric disorders (Kessler for in current genetic studies. Understanding the molecular et al., 2010). Finally, an increasing body of literature suggests embedding of risk, conferred by adverse life events and how that prenatal adversity, in the form of stress or mood and anxiety these interact with genetic vulnerability, may be important for disorders of the mother, is also a risk factor for psychiatric disor- the identification of the missing heritability observed in stress ders (Stein et al., 2014). A factor common to these early adver- disorders. One molecular mechanism that has come into focus sities is that they have all been associated with long-term for mediating long-term environmental effects is epigenetics changes in the regulation of the stress hormone system (Lupien (Slatkin, 2009). et al., 2009), as illustrated in Figure 1, which may be causally Epigenetics subsumes mechanisms of functional control over related to the development of disease. In addition to the strong the genetic information without changing DNA sequence. These effects of the environment, there is a significant genetic contribu- mechanisms include the post-translational modification of tion to the development of these disorders (Kendler et al., 2006; histone proteins as well as chemical modifications of single Sullivan et al., 2000). However, strong main genetic effects have nucleotides (most commonly in the form of DNA methylation not been observed for stress-related psychiatric disorders to or hydroxymethylation at cytosine residues), which alter the date, reflected by a lack of genome-wide significant associations chromatin structure and thus the accessibility of the DNA to in studies with sample sizes that have led to robust genetic transcriptional regulators. In the broader sense of epigenetic association signals for schizophrenia and bipolar disorder regulation, these mechanisms also include the regulation of tran- (Schizophrenia Working Group of the Psychiatric Genomics scription and translation by non-coding RNAs, as schematically Consortium, 2014; Ripke et al., 2013; Mu¨ hleisen et al., 2014). represented in Figure 2. We here intentionally include regulation The genetics of stress-related disorders are therefore confronted by non-coding RNAs because of their ability to regulate tran- with the so-called missing heritability that describes the lack of scriptional and translational output in post-mitotic neurons and strong effects in the kind of gene-association studies found in direct epigenetic modifiers to specific loci (Bird, 2007; Bonasio Neuron 86, June 17, 2015 ª2015 Elsevier Inc. 1343 Neuron Review Early life stress Figure 1. Stress and, in Particular, Early Life Trauma exposure Adversities Activate the Stress Hormone System and May Epigenetically Program the System toward a Lifelong Alteration of the Hormonal Response to Even Minor Stressors The neuropeptides corticotrophin-releasing hor- CRH GR GR Ultra-short negative mone (CRH) and vasopressin (AVP), released hsp90 AVP GR GR feedback on FKBP5 GR sensitivity from the hypothalamus in response to stress, hsp90 POMC within the cell activate the release of adrenocorticotropic hor- FKBP4 mone (ACTH) from the anterior pituitary gland, FKBP5 finally leading to an increased systemic cortisol secretion from the adrenal gland. Cortisol binds ACTH GR GR to steroid receptors, the mineralocorticoid re- hsp90 ceptor (MR) and the glucocorticoid receptor (GR), that act as transcriptional activators or repressors GRE GRE GRE in the nucleus through binding to glucocorticoid response elements. This influences the expres- sion of numerous genes involved in the stress Adrenal gland response, immune function, and metabolism. Binding of the GR and transcriptional activation CORT of, for example, FKBP5 provide an ultrashort feedback to the GR, terminating the stress response and secretion of cortisol. et al., 2010; Egger et al., 2004; Holliday, 2006; Jaenisch and Bird, Modification of Epigenetic Profiles by Severe Stress and 2003; Jenuwein and Allis, 2001; Peschansky and Wahlestedt, Trauma in Early Life—Potential Mechanisms 2014). Some epigenetic modifications, especially DNA methyl- In addition to a growing number of animal studies indicating ation, have been considered irreversible in the past, defining long-lasting epigenetic effects of early stressful environments, cellular identity in a multicellular organism. By now it has been a number of studies in humans now also suggest that such shown that even stable chemical modifications, such as DNA mechanisms may play a role in stress-related psychiatric disor- methylation, underlie highly dynamic regulation. This potential ders. In contrast to animal studies that can focus on brain tissue, reversibility makes these mechanisms suitable for encoding most human studies have been performed in mixed tissues that the long-term impact of the environment also in post-mitotic tis- are accessible to molecular investigation, such as peripheral sue such as neurons (Sweatt, 2013). Although often depicted blood and buccal cells, with only few studies investigating separately for clarity, epigenetic mechanisms form a complex post-mortem brain tissue. Initial studies followed hypothesis- interactive network with joint activities of different mechanisms driven, candidate-based approaches, but recent advances in contributing to the same transcriptional regulation. array- and sequencing-based techniques allowed the interroga- The field of epigenetics thus provides a possible molecular tion of epigenetic marks on a genome-wide level as recently re- framework of how genetic and environmental factors interact viewed in Klengel et al. (2014). Among the very first candidates and shape the risk for psychiatric disorders (Sweatt, 2013). implicated in stress-related epigenetic regulation were genes Epigenetics has been shown to play a decisive role in the involved in the stress- or hypothalamus-pituitary-adrenal (HPA) neuronal adaptations underlying learning and memory (Zovkic axis due to its prominent role in the pathophysiology of stress- and Sweatt, 2013), the response to environmental challenges related disorders. Other candidate gene-driven studies were (Champagne, 2010; Jirtle and Skinner,