br Funding Sources Lundbeck Foundation Center for Clinical I

Funding Sources Lundbeck Foundation Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) (R25-A2701 and R155-2013-16337), Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Mental Health Services, Capital Region of Denmark, and Faculty of Health and Medical Sciences, Department of Clinical Medicine, Copenhagen University.
Declaration of Interests
Contributors
Introduction Genes implicated in glucocorticoid regulation play an important role in regulating the physiological impact of social and environmental stress, and have become a focal point for investigating the role of stress in the etiology of disease (Moisiadis and Matthews, 2014). As such, a growing number of studies have identified DNA methylation of continine within the hypothalamic-pituitary-adrenal (HPA) axis as an important mechanism through which exposure to stressful physical and social environments may alter glucocorticoid regulation (Palma-Gudiel et al., 2015; Daskalakis and Yehuda, 2014; Zannas et al., 2016; Needham et al., 2015). What remains unclear, however, is the extent to which such epigenetic regulation might be associated with risk of various clinical diseases. In this systematic review, we outline the full range of clinical associations that have been reported in relation to DNA methylation of HPA axis genes in order to better understand the underlying biological and epigenetic pathways of stress-related disease, and to explore new avenues for diagnosis and treatment. The HPA axis involves several biochemical feedback pathways between the hypothalamus, anterior pituitary gland, and adrenal glands (Fig. 1). It is the major neuroendocrine system that controls stress reactivity and regulates stress hormone (i.e., glucocorticoid) levels within the body. However, as the HPA axis also regulates many fundamental bodily processes such as the immune system, mood and cognition, and the metabolic system (Smith and Vale, 2006), disruption or dysregulation of this system can often increase risk of disease. The pathways and feedback mechanisms of the HPA axis involve interactions between a number of hormones, proteins, and receptors. First, acute stress triggers the release of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus, with circulating levels of CRH largely being regulated by CRH binding proteins (CRH-BP) (Westphal and Seasholtz, 2006). CRH is transported via the hypophyseal portal system of blood vessels to the anterior pituitary gland, where it binds to CRH-R1 and CRH-R2 receptors (Papadopoulou et al., 2005). This causes the pituitary gland to secrete adrenocorticotropic hormone (ACTH; whose precursor is POMC) into the bloodstream, which in turn binds to ACTH-R receptors in the adrenal gland and stimulates the production of glucocorticoids (e.g., cortisol) by the adrenal cortex (Khorram et al., 2011). When high concentrations of glucocorticoids are achieved in the bloodstream (i.e., during stressful experiences), glucocorticoids bind to glucocorticoid receptors (GR) in the hippocampus, hypothalamus, and anterior pituitary gland in order to suppress further release of CRH and ACTH in a negative feedback loop that stabilizes glucocorticoid levels within an appropriate physiological range (Tasker and Herman, 2011). Cortisol levels are further regulated by the HSD11β2 enzyme, which degrades cortisol to cortisone, whereas HSD11β1 catalyzes the conversion of the inactive cortisone to active cortisol (Tomlinson et al., 2004). The glucocorticoid receptor (GR) resides in the cell cytoplasm. When bound to glucocorticoids, the GR translocates to the nucleus in a complex of co-chaperones that regulates the synthesis of a number of immune, inflammatory, and metabolic proteins through two genomic mechanisms of action (Fig. 2). First, the GR complex may act as a transcription factor that activates the transcription of immune- and metabolic-related genes by binding directly to glucocorticoid response elements (GREs) in nuclear DNA through a process called transactivation. Second, the GR complex may also repress the transcription of genes that code for immunosuppressive and pro-inflammatory proteins such as cytokines and prostaglandins through a process call transrepression, wherein the GR complex interacts with other transcription factors such as AP-1 and NF-κB to reduce their transcriptional activity without contacting the DNA itself (Ratman et al., 2013; Strehl and Buttgereit, 2013). Binding of the FKBP5 protein to this GR complex lowers the complex\'s affinity for cortisol and makes nuclear translocation of the GR complex less efficient (Wochnik et al., 2005), while also promoting nuclear translocation of the non-active GRβ splice variant (isoform), and thus decreasing overall GR signaling (Zhang et al., 2008). In this way, overexpression of FKBP5 proteins can lead to glucocorticoid resistance and decreased glucocorticoid sensitivity (Binder, 2009). Expression of FKBP5 mRNA is induced by glucocorticoids, however, leading to an ultra-short negative feedback loop wherein greater circulating levels of glucocorticoids induce greater FKBP5 protein expression, thus regulating GR signaling within an appropriate range (Vermeer et al., 2003).