The endogenous regulation of a specific gene is associated with a reduced risk of developing post-traumatic stress disorder following a terrifying experience.
In particular, traumatic memories of the experience are less severe.
Researchers from the University of Basel have reported these findings in the scientific journal PNAS.
Traumatic experiences, such as an accident, rape or torture, can become deeply entrenched in a person’s memory and cause symptoms of post-traumatic stress disorder (PTSD) even years later.
The stress hormone cortisol plays a vital role in the regulation of these memory processes, as demonstrated by a number of studies, including those from the research team led by Professor Dominique de Quervain at the University of Basel.
In their current project, de Quervain’s team took a closer look at the genes involved in cortisol signaling. Specifically, they determined the extent to which these genes are subject to chemical regulation by methyl groups on the DNA molecule.
Vanja Vukojevic, one of the lead authors of the study, analyzed DNA methylation in two groups of people affected by trauma, namely 463 survivors of the Ugandan civil war and 350 survivors of the genocide in Rwanda.
In both groups, those who showed stronger regulation of the gene NTRK2 were at less risk of developing PTSD.
The researchers were also able to rule out with a high degree of certainty that the trauma itself leads to an altered regulation of this gene.
They found no link between the severity of the trauma and the extent of DNA methylation, which suggests that the latter existed before the traumatic experience.
Several basic studies have already shown that the gene NTRK2 plays a key role in memory formation.
Indeed, in the current study, individuals with stronger regulation of this gene had fewer traumatic memories.
The researchers also found that the regulatory mechanism – DNA methylation on the gene NTRK2 – was also linked to memory in 568 non-traumatized individuals. Those with stronger methylation of the gene performed worse when it came to remembering images they had seen previously. They also showed altered brain activity in regions important for memory during the tests.
These results suggest that increased regulation of the NTRK2 gene reduces memory formation. As a result, traumatic experiences do not become as entrenched in the memory, reducing the risk of developing PTSD.
The researchers hope that this mechanism will contribute to the development of new therapies, which may also help in cases of existing PTSD by preventing recurrent unpleasant recollections from further cementing the traumatic memory.
It has been implicated that the epigenetic mechanism of DNA methylation is associated with childhood maltreatment in both animal and human studies .
Current evidence also demonstrates that stressful events during childhood and adulthood have an impact on the increased risk of psychiatric disorders such as depression .
Numerous studies with a candidate-gene approach suggested that the epigenetic mechanism of DNA methylation in various genes, such as BDNF, NR3C1, OXTR, and SLC6A4, is associated with depression [9,39-41].
Fuchikami et al.  found that DNA methylation of the BDNF gene can be used as a biomarker for differentiating healthy controls from patients with depression due to different methylation levels of CpG units within CpG I of the BDNF gene between healthy controls and patients with depression.
In an animal study, Roth et al.  demonstrated that elevated DNA methylation within the Bdnf gene is associated with stressful early-life events for rats by using an animal model of childhood maltreatment.
In accordance with Roth et al.’s  results, subsequent animal studies verified that the Bdnf gene is associated with alterations in DNA methylation [44,45]. It should be noted that the BDNF gene is a well-known potential marker for playing a role in the pathophysiology of depression in both animal and human studies .
In the context of animal models, it has also been implicated that stressful early-life events can regulate the DNA methylation level of genes, such as the Avp, Esr1, Gad1, Gdnf, Nr3c1, and SLC6A4 genes, in animal studies [47-52].
In addition, Tyrka et al.  demonstrated that reduced methylation levels of the NR3C1 gene were linked to childhood maltreatment and depressive disorders in human adults (n=340). Na et al.  also showed that hypomethylation of the NR3C1 gene in blood samples was linked to patients of depression (n=45), when matched to healthy controls (n=72).
It has been suggested that declined hippocampal glucocorticoid receptor expression was linked to depression and suicide, where the NR3C1 gene encodes glucocorticoid receptor . In a postmortem hippocampus study, McGowan et al.  explored whether epigenetic differences exist in the promoter region of the NR3C1 gene by matching suicide victims (n=12) with a history of childhood abuse to healthy controls (n=12).
McGowan et al.’s  analysis detected elevated cytosine methylation in abused suicide victims at two discrete CpG regions in the promoter site of the NR3C1 gene, hypothesizing that DNA methylation may prevail into adulthood. In accordance with McGowan et al.’s  study, Weaver et al.  observed that epigenetic alterations in the Nr3c1 gene is modulated by early life events in an animal study of epigenetic regulation in related genomic sites.
Given that BDNF-NTRK2 signature has been linked to depression and suicide, Ernst et al.  investigated whether NTRK2 expression is significantly reduced in suicide patients when matched to healthy controls and whether methylation is linked to the downregulation.
In a postmortem case-control study, Ernst et al.  evaluated microarray data to test the hypothesis by using HG-U133 chips (Affymetrix, High Wycombe, England). Ernst et al.  reported the downregulated expression of the NTRK2 gene in suicide completers and observed that this downregulation was modulated by the methylation state at two specific CpG dinucleotides of the promoter site in the NTRK2 gene in the frontal cortex of suicide completers. It has been suggested that a truncated polymorphism of the NTRK2 gene is expressed in astrocytes.
In a methylation-sensitive restriction enzyme-based study, Sabunciyan et al.  tested the genome-wide DNA methylation scan with a microarray platform (containing 3.5 million CpGs) by matching postmortem frontal cortex samples (n=39) of depressive patients to healthy controls (n=26).
Sabunciyan et al.  observed the greatest difference in the PRIMA1 gene with 12–15% elevated DNA methylation in depressive patients; however, this observation did not remain significant after multiple testing correction.
Because DNA methylation alterations are unlikely to occur in the frontal cortex of depressive patients, the major target might be in other brain regions such as hippocampus and amygdala .
Furthermore, several epigenome-wide association studies (EWAS) have been conducted to identify the probable interrelationship between DNA methylation and depression [59-63]. In an EWAS study, Uddin et al.  assessed genome-wide methylation profiles of about 14,000 genes and demonstrated different DNA methylation patterns between patients with a lifetime history of depression (n=33) and healthy controls (n=67) by using methylation microarrays. In another EWAS study, Numata et al.  assessed genome-wide methylation profiles of 431,489 CpG sites and found lower DNA methylation at 363 CpG sites in medication-free patients with depression (n=20) compared to healthy controls (n=19) by using methylation microarrays, suggesting that the DNA methylation biomarkers can be used to distinguish patients with depression from healthy controls with good performance.
Moreover, Byrne et al.  reported lower global DNA methylation levels in female patients with depression, but not among male subjects, in an Australian EWAS study of 24 monozygotic twin pairs discordant for depression. Sabunciyan et al.  also identified hypermethylation of the PRIMA1 gene in a pilot EWAS study; however, this result could not be confirmed in the replication data. Finally, Tseng et al.  detected that there was a decrease in global DNA methylation in older patients with severe depression, but not in younger patients, in a Taiwanese EWAS study.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761788/
More information: Vanja Vukojevic el al., “NTRK2 methylation is related to reduced PTSD risk in two African cohorts of trauma survivors,” PNAS (2020). www.pnas.org/cgi/doi/10.1073/pnas.2008415117