methylation of il18 but lower methylation of h19 and il18 is associated with deployed veterans who developed ptsd< nr3c1 lower methylation levels of nr3c1 1b and 1c promoters is associated with ptsd; fathers with ptsd have offspring with higher nr3c1 1f promoter methylation; lower levels of nr3c1 1f promoter methylation is associated with ptsd in combat veterans; higher levels of nr3c1 methylation in male (but not female) rwandan genocide survivors is associated with decreased ptsd risk spatc1l higher methylation is associated with ptsd symptoms. hla-dpb1 higher methylation is associated with ptsd symptoms. histone modifications histone acetylation is performed by histone acetyl transferases (hats) and histone deacetylation is carried out by histone deacetylases (hdacs). in rodent ptsd models, it has been found that an increase in histone acetylation is associated with fear conditioning. histone acetylation can be involved in all parts of fear memory, including the development to memory extinction. it can also play a role in long-term potentiation (ltp). it was also observed that hdacs increase memory formation in fear extinction and hdac inhibitors (hdaci) have shown evidence for modifying memory extinction, a possible treatment for ptsd. nervous system structures affected by ptsd hypothalamus-pituitary-adrenal axis the hypothalamus-pituitary-adrenal (hpa) axis is a neuroendocrine system largely involved in ascertaining the levels of cortisol circulating the body at any given point in time. as cortisol plays a key role in the stress response, so does the hpa axis. the dysregulation of the hpa axis has been found to be characteristic of several stress disorders, including ptsd. this system works under a negative feedback loop structure. hence, this hpa axis dysregulation may take the form of amplified negative inhibition and result in down-regulated cortisol levels. epigenetic modifications play a role in this dysregulation, and these modifications are likely caused by the traumatic/stressful experience that triggered ptsd. immune dysregulation by hpa axis modifications ptsd is often linked with immune dysregulation. traumatic experiences can induce epigenetic changes at the gene loci that are immune-related which can lead to immune dysregulation and an increased risk of ptsd. trauma exposure can also disrupt the hpa axis, thus altering peripheral immune function. the effect of ptsd on immune function arises in at least two ways: 1) continuous disturbances on the hpa axis can dysregulate peripheral immune function, and 2) the effects of immune dysregulation in the periphery can lead to increased development of ptsd because of alterations in brain function. ptsd-associated changes in immune cells found in blood or saliva can serve as biomarkers that trigger epigenetic changes which are involved in the pathogenesis of ptsd. these unique biomarkers serve as means of identifying ptsd subtypes. beyond identifying subtypes, these distinct biomarkers can potentially be used to develop ptsd treatments. epigenetic modifications have been observed in immune-related genes of individuals with ptsd. for example, deployed military members who developed ptsd have higher methylation in the immune-related gene interleukin-18 (il-18). this has interested scientists because high levels of il-18 increase cardiovascular disease risk, and individuals with ptsd have elevated cardiovascular disease risk. thus, stress-induced immune dysregulation via methylation of il-18 may play a role in cardiovascular disease in individuals with ptsd. additionally, an epigenome-wide study found that individuals with ptsd have altered levels of methylation in the following immune-related genes: tpr, clec9a, apc5, anxa2, tlr8, il-4, and il-2. this again shows that immune function in ptsd is disrupted, especially by epigenetic changes that are likely stress-induced. genes affected by ptsd nr3c1 nr3c1 is a transcription factor that encodes a glucocorticoid receptor (gr) and contains many gr response elements. npas4 is another regulatory transcription factor also responsible for the regulation of grs. stress-induced changes in nr3c1 and npas4 methylation have been shown to alter stress sensitivity. this response differs between short-lived stress exposure and chronic stress exposure. in response to short lived stress, the nr3c1 promoter is more hydroxymethylated which is a modification associated with increased transcription of gr-associated genes. thus, short lived stress exposure increases stress sensitivity. conversely, in response to chronic stress, the npas4 promoter has been presumed to be increased in methylation, a modification which is associated with inhibitory regulation of grs. thus, chronic stress exposure decreases stress sensitivity. these distinctions are important in understanding the epigenetic patterns of stress and genetic interactions with ptsd triggers. overall, in the hippocampus of chronically stressed animals, the 3′-utr (untranslated region of dna) of the glucocorticoid receptor nr3c1 showed increased hydroxymethylation, which led to increased transcription and thus, the disruption of stress tolerance and increased risk of disorders such as ptsd. however, early life stress increases methylation of the 1f promoter in this gene (or the 17 promoter analog in rodents). because of its role in stress response and its link to early life stress, this gene has been of particular interest in the context of ptsd and has been studied in ptsd of both combat veterans and civilians. in studies involving combat veterans, those who developed ptsd had lowered methylation of the nr3c1 1f promoter compared to those who did not develop ptsd. additionally, veterans who developed ptsd and had higher nr3c1 promoter methylation responded better to long-term psychotherapy compared to veterans with ptsd who had lower methylation. these findings were recapitulated in studies involving civilians with ptsd. in civilians, ptsd is linked to lower methylation levels in the t-cells of exons 1b and 1c of nr3c1, as well as higher gr expression. thus, it seems that ptsd causes lowered methylation levels of gr loci and increased gr expression. the methylation of gr in t-cells are investigated because of its role in regulating cell immunity which, as such, stores cellular memory with environmental factors. t-cell fragments from individual cell populations are preferred over homogenized tissue because of the drastic variation in dna methylation patterns between different cell fragments. although these results of decreased methylation and hyperactivation of gr conflict with the effect of early life stress at the same loci, these results match previous findings that distinguish hpa activity in early life stress versus ptsd. for example, cortisol levels of hpa in response to early life stress is hyperactive, whereas it is hypoactive in ptsd. thus, the timing of trauma and stress—whether early or later in life—can cause differing effects on hpa and gr. fkbp5 fkbp5 encodes a gr-responsive protein known as fk506 binding protein 51 (fkbp5). fkbp5 is induced by gr activation and functions in negative feedback by binding gr and reducing gr signaling. there is particular interest in this gene because some fkbp5 alleles have been correlated with increased risk of ptsd and development of ptsd symptoms—especially in ptsd caused by early life adversity. therefore, fkbp5 likely plays an important role in ptsd. as mentioned previously, certain fkbp5 alleles are correlated to increase ptsd risk, especially due to early life trauma. it is now known that epigenetic regulation of these alleles is also an important factor. for example, cpg sites in intron 7 of fkbp5 are demethylated after exposure to childhood trauma, but not adult trauma. additionally, methylation of fkbp5 is alters in response to ptsd treatment; thus methylation levels of fkbp5 might correspond to ptsd disease progression and recovery. adcyap1 and adcyap1r1 pituitary adenylate cyclase-activating polypeptide (adcyap1) and its receptor (adcyap1r1) are stress responsive genes that play a role in modulating stress, among many other functions. additionally, high levels of adcyap1 in peripheral blood is correlated to ptsd diagnosis in females who have experienced trauma, thus making adcyap1 a gene of interest in the context of ptsd. epigenetic regulation of these loci in relation to ptsd still require further investigation, but one study has found that high methylation levels of cpg islands in adcyap1r1 can predict ptsd symptoms in both males and females. alcohol use disorder alcohol dependence and stress interact in many ways. for example, stress-related disorders such as anxiety and ptsd are known to increase risk of alcohol use disorder (aud), and they are often co-morbid. this may in part be due to the fact that alcohol can alleviate some symptoms of these disorders, thus promoting dependence on alcohol. conversely, early exposure to alcohol can increase vulnerability to stress and stress-related disorders. moreover, alcohol dependence and stress are known to follow similar neuronal pathways, and these pathways are often dysregulated by similar epigenetic modifications. hdac histone acetylation is dysregulated by alcohol exposure and dependence, often through dysregulated expression and activity of hdacs, which modulate histone acetylation by removing acetyl groups from lysines of histone tails. for example, hdac expression is upregulated in chronic alcohol use models. monocyte-derived dendritic cells of alcohol users have increased hdac gene expression compared to non-users. these results are also supported by in vivo rat studies, which show that hdac expression is higher in alcohol-dependent mice that in non-dependent mice. furthermore, knockout of hdac2 in mice helps lower alcohol dependence behaviors. the same pattern of hdac expression is seen in alcohol withdrawal, but acute alcohol exposure has the opposite effect; in vivo, hdac expression and histone acetylation markers are decreased in the amygdala. dysregulation of hdacs is significant because it can cause upregulation or downregulation of genes that have important downstream effects both in alcohol dependence and anxiety-like behaviors, and the interaction between the two. a key example is bdnf (see "bdnf" below). bdnf brain-derived neurotrophic factor (bdnf) is a key protein that is dysregulated by hdac dysregulation. bdnf is a protein that regulates the structure and function of neuronal synapses. it plays an important role in neuronal activation, synaptic plasticity, and dendritic morphology—all of which are factors that may affect cognitive function. dysregulation of bdnf is seen both in stress-related disorders and alcoholism; thus bdnf is likely an important molecule in the interaction between stress and alcoholism. for example, bdnf is dysregulated by acute ethanol exposure. acute ethanol exposure causes phosphorylation of creb, which can cause increased histone acetylation at bdnf loci. histone acetylation upregulates bdnf, in turn upregulating a downstream bdnf target called activity-regulated cytoskeleton associated protein (arc), which is a protein responsible for dendritic spine structure and formation. this is significant because activation of arc can be associated with anxiolytic (anxiety-reducing) effects. therefore, ethanol consumption can cause epigenetic changes that alleviate stress and anxiety, thereby creating a pattern of stress-induced alcohol dependence. alcohol dependence is exacerbated by ethanol withdrawal. this is because ethanol withdrawal has the opposite effect of ethanol exposure; it causes lowered creb phosphorylation, lowered acetylation, downregulation of bdnf, and increase in anxiety. consequently, ethanol withdrawal reinforces desire for anxiolytic effects of ethanol exposure. moreover, it is proposed that chronic ethanol exposure results in upregulation of hdac activity, causing anxiety-like effects that can no longer be alleviated by acute ethanol exposure. potential epigenetic drug treatments