ReviewEpigenetics of Posttraumatic Stress Disorder: Current Evidence, Challenges, and Future Directions
Section snippets
Why Examine Epigenetics in PTSD?
The complex phenotype of PTSD is thought to emerge from interactions among multiple genetic and environmental factors. Disentangling the mechanisms through which these factors contribute to PTSD pathogenesis could enable identification of individuals predisposed to show maladaptive responses to trauma. Although heritability studies have repeatedly supported a genetic contribution to the pathogenesis of the disorder (5, 6), efforts to consistently identify specific genetic predictors of the
Overview of Epigenetic Studies in PTSD
To date, most epigenetic studies in PTSD have examined the methylation status of cytosine residues of genomic DNA. The particular interest in DNA methylation in the context of PTSD was spurred by numerous studies in animals and humans showing that DNA methylation changes can be embedded by early adverse experiences and these markers may confer vulnerability to subsequent life adversity (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). Although DNA methylation initially was thought to be a
Examining Epigenetic Mechanisms of PTSD in Humans
Human studies are crucial for understanding epigenetic processes in PTSD, but the tissue-specific nature of epigenetic modifications and the inability to access brain tissue of living humans impede the ability of such studies to offer mechanistic insights. This shortcoming may be partially overcome by examining postmortem brain tissue. The need for postmortem studies in PTSD has long been highlighted (47), but, to our knowledge, no studies so far have examined epigenetic markers in postmortem
Translating Epigenetic Findings in PTSD
The limitations inherent to examining mechanisms of PTSD in humans create the need for animal models with good construct validity for PTSD, such as the Pavlovian fear conditioning, avoidance learning, and predator-exposure models. A detailed description of these models and related epigenetic studies is beyond the scope of this article and has been provided elsewhere (72, 73). The rodent studies have provided valuable insights into the neural circuitry and epigenetic mechanisms that are involved
Gene-Trauma-Epigenetic Interactions in PTSD
An important concept that emerges from epigenetic studies in PTSD is that DNA methylation changes induced by trauma may be allele-specific and may interact in a complex manner with genetic background and trauma exposure. These interactions may affect the expression of genes involved in stress responses, neurotransmitter function, and immune regulation, eventually contributing to vulnerability/resilience endophenotypes and, ultimately, to a continuum of phenotypes ranging from PTSD to
Timing of Trauma and the Need for Longitudinal Studies
An important point that has not been adequately addressed by previous studies is the timing of traumatic exposure and its temporal relationship to epigenetic changes and development of PTSD. Sensitive periods of trauma exposure previously were highlighted in gene-environment interaction; in particular, trauma early in life was associated with lasting epigenetic changes and more robust effects on PTSD phenotypes (10, 11, 57, 76, 77, 78, 79, 80, 81, 82). The importance of early trauma on
Limitations of Epigenetic Studies in PTSD AND FUTURE DIRECTIONS
An increasing body of evidence supports a role for epigenetic regulation in PTSD. Although these findings offer an exciting prospect for future research endeavors, several limitations of epigenetic studies in PTSD should be highlighted. First, most studies to date use either animal models or blood tissue in humans. These studies are inherently limited by the tissue specificity of epigenetic changes and the inability to interrogate brain tissue in living humans. This shortcoming may be overcome
Conclusions
Beyond their value in promoting mechanistic understanding and use as disease biomarkers, epigenetic modifications are potentially reversible and represent attractive candidates for the development of new treatments for psychiatric disorders. Studies in rodents have used epigenetic drugs successfully to target DNA methyltransferases or histone-modifying enzymes (72, 73). Such manipulations showed that DNA methylation and histone acetylation are involved in every step of fear memory, from the
Acknowledgments and Disclosures
This work was supported by a European Research Council starting grant (Grant No. 281338, Gene x environment interactions in affective disorders - elucidating molecular mechanisms GxE molmech).
The authors report no biomedical financial interests or potential conflicts of interest.
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2022, iScienceCitation Excerpt :Evidence from clinical imaging research and studies using animal models of aspects of PTSD suggests that PTSD pathophysiology manifests from a dysregulation of the amygdala in response to trauma-related or emotional cues (Verbitsky et al., 2020; Del Casale et al., 2022; Johansen et al., 2011; Leite et al., 2022; Gonda et al., 2022; Yehuda et al., 2015). Accumulating evidence indicates that epigenetic (dys)regulation could play a pivotal role in the pathogenesis of PTSD (Zannas et al., 2015; Howie et al., 2019). However, over the last decade, new research has shifted attention from the epigenome to the role of RNA modifications, collectively known as the epitranscriptome, in modulating brain function and behavior (Zhao et al., 2017; Madugalle et al., 2020; Livneh et al., 2020; Jonkhout et al., 2017; Murakami and Jaffrey, 2022).