factors. Among these, environmental factors such as early stressful life events, including childhood sexual and physical abuse, have consistently been identified to increase risk for negative mental health outcomes, including suicidal ideation,
and suicide completion.
of the abuse has been shown to moderate the risk for suicidal behavior. Exactly how these adverse events during developmental periods result in heightened risk for suicide later in life is still largely unknown, although a growing body of evidence suggests that environmental stressors, such as early life adversity (ELA), regulate behavior through epigenetic processes.
Epigenetics refers to the processes that allow the genome to respond and adapt the functions of genes in response to environmental cues.12 The chemical structure surrounding the DNA, called the epigenome, facilitates these activities by increasing or decreasing gene expression via three commonly described mechanisms: DNA methylation; histone modification; and non-coding RNAs.
Briefly, histone modifications alter the structure of chromatin and influence chromatin conformation.13 Chromatin’s active “open” state allows the transcription machinery to access genes and synthesize mRNA strands, while chromatin’s inactive “closed” state prevents this process from occurring, inducing a reduction in gene expression. These changes in chromatin structure largely result from post-translational modifications of particular histone tail amino acids, which lead to a loosening or tightening of the structure.14
DNA methylation refers to the transfer of methyl groups (CH3) to cytosine (C) nucleotides of cytosineguanine dinucleotides (CpG) within the genome.15 DNA methylation in the regulatory regions of genes is thought to modify the access of transcription factors and the recruitment of transcriptional machinery to the DNA, thus modifying gene expression.16
In general, DNA methylation has been associated with repression of gene expression;17 however, there is evidence suggesting increased gene expression as a result of methylation in regulatory regions, as well.16
While mechanisms underlying the link between environmental factors and behavioral modification later in life are poorly understood, current evidence supports the notion that alterations to the hypothalamic-pituitary-axis (HPA) stress response, and adaptive neurodevelopment in response to ELA may be driven by epigenetic mechanisms. With this in mind, it is the purpose of this review to elaborate on this growing body of evidence by discussing recent advances in research targeting the role of epigenetic processes in the relationship between ELA and suicidal behavior.
Because genes implicated in the stress response and neurodevelopment represent the strongest evidence supporting an epigenetic link between ELA and suicide, this review will focus on discussing these genes. We will then discuss the role of epigenetics in anti-depressant interventions. Lastly, future directions in the epigenetic investigation of suicide will be discussed.
Stress Response and the HPA Axis
The HPA is the primary biological driving force of the stress response.18 Under normal conditions, stressors trigger hypothalamic release of corticotropin-releasing factor (CRF), which then stimulates the pituitary gland, resulting in the release of adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH travels to the adrenal cortex, which then pumps glucocorticoids into the bloodstream. These glucocorticoids act on the hippocampus, decreasing the release of CRF and ACTH, and reducing the stress response back to basal levels through a negative feedback mechanism. However, in depressed and other clinical populations, this process may become aberrant.19,20
Accordingly, in depressed populations, the basal level of the stress response has often been reported to be elevated when compared with healthy controls, indicating a possible HPA baseline overreactivity.21 Findings from animal and human studies suggest that the sensitization of the HPA in populations with mood and anxiety disorders may be primed by ELA development.19
Given the strong relationship between depression, ELA, and altered stress response, genes that assist in regulating HPA activity represent prime candidates for epigenetic studies of suicide. One of the best characterized genes in this line of inquiry is the glucocorticoid receptor (GR) gene.
ELA and Epigenetic Reprogramming of GR
GR in the hippocampus encodes the neuronal receptor that binds glucocorticoids during the stress response, driving the HPA negative feedback mechanism that reduces the stress response to basal levels.22 Given the vital regulatory role of glucocorticoids in the HPA stress response, studies have focused on the role of aberrant GR expression in the hippocampi of animals with variation in early environment; those animals exposed to stressors; and human populations with histories of ELA. This work has generated consistent evidence suggesting that epigenetic alteration of hippocampal GR expression in response to ELA results in the reprogramming of HPA stress responses involved in a range of deleterious outcomes, including suicide.23
Evidence linking ELA to epigenetic reprogramming of hippocampal GR was first reported by our group in 2009.23 This study identified decreased hippocampal GR expression among suicide victims with a history of ELA, compared with suicide victims without ELA history and healthy controls. This decrease in hippocampal GR correlated to hypermethylation in specific CpG sites of a GR promoter regulating the expression of an untranslated exon 1 variant (1F) that is primarily expressed in the hippocampus.
The differential methylation mapped to sites where transcription machinery binds to activate the promoter.23 These results echo findings from previous work in maternal behavior models in rats indicating that variation in maternal behavior linked to depressive-like behavior,24 elevated stress response, and decreased GR expression in adult offspring,20 resulted in similar epigenetic changes occurring at the same regulatory region of the rat GR gene.25
These pivotal studies have provided compelling evidence that epigenetic regulation of GR in the hippocampus may play a key role in sustained maladaptive HPA stress responses, which may increase risk for suicide.
More recent investigation has further elaborated on these observations. A recent study examining epigenetic alteration to hippocampal GR among suicide victims with major depressive disorder (MDD) suggested that the epigenetic marks outlined above may only emerge among those with histories of ELA.26 Similarly, more recent work from our group has identified that methylation of specific GR’s promoter variants other than the 1F are also unique to suicide victims with ELA.27 These studies offer compelling evidence to suggest that altered hippocampal GR expression may be particular to the presence of ELA.
Taken together, both animal and human methylation studies investigating GR provide compelling evidence suggesting a role of epigenetic alterations associated with ELA and suicide risk. Further, this evidence is consistent with evidence suggesting an important role of the HPA stress axis in suicide. Most importantly, this work indicates that ELA may increase risk of suicide by epigenetically regulating hippocampal GR, which in turn may be associated with HPA reactivity. However, suicide predisposition may be also associated with epigenetic modifications in other genes.
Importance of Brain-Derived Neurotrophic Factor
The brain-derived neurotrophic factor (BDNF) plays a vital role in regulating plastic and neurodevelopmental functions in the CNS, with aberrant expression of the BDNF gene linked to the pathogenesis of psychiatric and neurodegenerative disorders.28 Altered expression has also been reported for a gene (TrkB) that codes for BDNF’s receptor.6,29 Given abnormal BDNF expression in psychiatric conditions, and potential mediation of this activity by TrkB, much research has focused on elucidating possible epigenetic regulation of both genes in suicide.
Suicide studies focusing on BDNF and TrkB have shown decreased expression of both genes in the hippocampus and prefrontal cortex (PFC) of suicide completers.6,30,31 Similar decreases in BDNF expression have been revealed in rodent models inducing long-term depression-like behaviors through exposure to chronic psychosocial stress.32,33 Investigation of molecular mechanisms underlying depressive-like behavior among socially stressed rodents has revealed that reduced BDNF expression in the hippocampus and PFC are driven by hypermethylated regulatory regions of BDNF and histone modifications resulting in “closed” chromatin.32–34
Thus, evidence from rodent models of stress-induced depression indicates that stressful experience may affect BDNF expression in brain areas implicated in stress regulation through epigenetic processes. A critical question related to the subject of this review is whether suicide completers show similar epigenetic regulation of BDNF.
Recent studies by our group have suggested reduced expression of TrkB in the PFC of suicide completers which has been associated with hypermethylation of two critical regulatory regions of the gene, as well as markers indicating a closed chromatin state.6,30
More recent studies indicated a hypermethylation regulated decrease in BDNF activity among suicide completers in the Wernicke area of the brain, with a follow-up study showing no reduction of TrkB expression in the same area.35,36
Together, these studies suggest that epigenetic alteration of TrkB in suicide completers is brain-region-specific and may be unique to stress-regulating areas, whereas altered BDNF expression may occur more globally. Given the role of TrkB as a BDNF receptor, future research may benefit from further exploring how both the TrkB and BDNF genes are epigenetically regulated to alter BDNF activity among suicides. A direct link between epigenetic regulation of BDNF and/or TrkB and ELA in humans has yet to be established. The work summarized above in animal models is highly suggestive that such a link exists; further work is needed to strengthen this argument.
The findings above suggest a stable relationship between ELA, epigenetic changes, and behavioral phenotypes, such as suicidal behavior. However, these effects may be reversible through intervention. Depressive-like behavioral phenotypes typically observed in rat pups reared by mothers who engaged in less licking and grooming maternal behaviors, were reversed when transferred into the care of more nurturing mothers during critical developmental windows. These changes were accompanied by decreased methylation at previously hypermethylated sites in the GR’s regulatory region, restoring normal gene expression.37,38
Similar reductions of depressive behavior and restoration of BDNF expression in the PFC has been observed using a similar cross-fostering model in rats exposed to maternal maltreatment.33 Pharmacological intervention has also been shown to reverse deleterious outcomes of ELA through epigenetic processes.
Mice exposed to chronic social stress showed a reduction of social-defeat-associated behaviors and restored hippocampal BDNF expression following chronic, but not acute, imipramine treatment.34 Further work has revealed similar effects on BDNF expression by a wide variety of drug classes, including monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SS-RIs), and others.29 Recently, it has been revealed that suicide victims who were on antidepressants showed a more “open” chromatin state when compared with controls and victims who were not on antidepressants.30 These studies indicate that a number of pharmaceutical agents may rely, in part, on epigenetic regulation of BDNF to produce their therapeutic effects.
Different drugs may alter expression of the same gene through different molecular and epigenetic mechanisms. More work is needed to characterize how different pharmaceutical agents uniquely affect the epigenome. Nevertheless, this research reveals potential new avenues of treatment for conditions that increase risk for suicide.
Although not as well-characterized as the HPA, epigenetic regulation of other brain systems has been observed. Aberrant activity of the serotonergic and GABAergic systems, which work together to regulate nervous system arousal, is commonly linked to depression and suicide, and appear to be under some degree of epigenetic regulation.40–42 Our group has also investigated the epigenetic regulation of genes in the polyamine system, which like HPA, is a stress-response system, critical for proper cellular functioning.43 Although compelling, this work has not yet yielded solid evidence supporting a direct link to ELA. Continued effort will be needed to elucidate a direct link between ELA and epigenetic regulation of these systems.
Recently, different DNA methylation mechanisms that influence gene expression have been identified. Accordingly, 5-hydroxymethylcytosine (5-HMC) is a newly identified epigenetic modification that may serve as either an intermediary to active demethylation or a repressor of gene expression.44 MicroRNAs (miRNAs) have recently been identified as a unique class of gene expression regulators thought to play a pivotal role in neuronal development, survival, and plasticity, and have been implicated in psychiatric disorders.45 Together, 5-HMC and miRNAs represent a window into processes that may underpin the epigenome and will likely provide invaluable insight for investigation of altered gene expression in psychiatric disorders and suicide.
Another crucial recent development in epigenetic research is the advent of high-throughput next-generation sequencing techniques. In brief, these sequencing techniques will allow researchers to interrogate the entire genome, yielding a vastly increased number of candidate genes on which to focus, while simultaneously screening for epigenetic modifications.46 This technology is rapidly becoming more cost-effective and will become a standard very shortly, allowing investigators to examine the role of epigenetics in suicide in much greater detail.
Suicide is the result of many convergent factors with environmental influences consistently linked to enhanced risk for suicide. A great deal of suicide research has focused on how ELA affects gene expression through epigenetic processes leading to increased risk for suicide attempts and completions. This work has built a strong case suggesting epigenetic regulation of genes is involved in stress response and neuronal growth.
While these effects may be reversible through intervention, at this stage we lack sufficient empirical data suggesting that this may be the case for all epigenetic regulatory changes. Improved sequencing technology will allow investigators to explore the role of epigenetics in suicide and, potentially, open up new avenues of epigenetic treatment for conditions that enhance risk for suicide.
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