Trauma Through the Ages: Inheriting the Epigenetic Scars of our Ancestors

Image author: Madeline Chan

Written by Jenna Bienstock and Sofia Labricciosa

CW: This paper discusses mental illness including PTSD, as well as the Holocaust

Abstract 

The prevalence of mental illness is rising among youth, while the search for remedies continues. Recently, the study of environmental epigenetics – changes in DNA resulting from environmental factors, has become increasingly relevant in understanding the origins of psychiatric disorders. Exposure to traumatic events often yields psychological burdens, but may also result in epigenetic modifications that can be inherited by offspring. Some of these heritable modifications have been associated with increased risk of post-traumatic stress disorder. Implementing a socially-enriched parenting style may help alleviate environmentally-induced alterations to an individual’s epigenome, and prevent the further inheritance of disease to their descendants, disrupting the cycle of trauma. 

Introduction 

Society is in a constant cycle of different ethnic groups experiencing trauma, commemorating the traumatic events, and attempting to prevent the trauma from recurring. When a community of people experience shared trauma, such as Jewish survivors of the Holocaust, emotional scars persist and incur lasting changes to both their own and subsequent generations’ genetic profiles.1 Post-traumatic stress disorder (PTSD) can be the result of extreme or prolonged trauma occurring during a period of vulnerability and is dependent on the severity of the traumatic experience, the age of occurrence, genetic vulnerability, or stress.2 PTSD often displays itself as symptoms of depression, anxiety, extreme sensitivity to various triggers, substance abuse issues, and poor emotional regulation.2 Environmental factors play a key role in gene expression and have the power to permanently alter an individual’s epigenome, leading to heritable modifications associated with phenotype and disease. Included in this piece is a discussion on trauma-related epigenetic alterations giving rise to the development of psychiatric disorders such as PTSD, as well as potential first steps in narrowing the association between trauma-induced epigenetics and social factors, in order to break society’s cycle of trauma. 

Epigenetics 

The study of epigenetics outlines the environmental factors that play an important role in an individual’s gene expression and provides a critical perspective in disease analysis.3,4 As a result, epigenetics may be used to explain the transgenerational effects of environmental exposures on phenotype development, contrary to the “genetic determinism” paradigm, which implies that genes lead to the development of traits independent of environmental factors.4 Epigenetic mechanisms can alter phenotype by upregulating or down regulating expression of specific genes without changing the genetic sequence.3 Once environmental factors permanently alter an individual’s epigenome, some of these alterations can be passed to their children. Changes in somatic cell epigenomes are often restrained within an individual, however, epigenetic changes in germline cells, such as changes in cells involved in fetal sex determination, may be passed on.1

In order to understand inherited trauma, the symptoms of initial trauma survivors should be analyzed. Jewish survivors of the Holocaust living in the United States were found to experience a higher quality of life than the average American and could function normally in their daily activities.1 However, survivors were shown to become incredibly vulnerable and emotionally reactive if faced with situations of heightened stress or perceived threats. Further studies in children of Holocaust survivors who did not present with day-to-day symptoms of PTSD, found that they were more likely to develop PTSD than the average American when faced with a traumatic experience.1 These studies indicate that the biological ramifications of trauma may have the potential to be passed to later generations. 

Trauma-Related Epigenetic Modifications Connected to Psychiatric Conditions Traumatic environmental exposures are important contributors in determining whether an epigenetic mechanism, such as DNA methylation, may lead to psychiatric ramifications.5 Studies in laboratory animals demonstrate the heritability of trauma via DNA methylation.6 A European study concluded that chronic and unpredictable maternal stressors and unpredictable maternal separation (MSUS) could induce behavioural changes in trauma-exposed individuals and in their proceeding offspring. Upon reaching adulthood, altered DNA methylation was observed in the promoter regions of certain candidate genes in the first-generation (F1) male offspring descending from mothers subjected to MSUS (F0).6 In particular, the candidate gene methyl CpG-binding protein 2 (MeCP2) displayed altered methylation.6 MeCP2 is a transcriptional regulator that plays a key role in stress regulation; a deficiency of MeCP2 expression results in a heightened stress response.7 Methylation alterations were observed between both the F1 male germline and the second-generation (F2) male germline descending from the MSUS-exposed mothers, in comparison to control mice.6 F2 mice displayed reduced MeCP2 mRNA expression.6 This evidence suggests that ancestral trauma may, in part, contribute to the development and expression of psychiatric disorders and behavioural changes. Similarly, a small study of Holocaust survivors revealed that both parents and offspring expressed abnormal methylation patterns of FK506 binding protein 5 (FKBP5).8 FKBP5 has been previously linked with PTSD by moderating glucocortioid receptor activity in response to stressors.9,10 Holocaust survivors displayed elevated FKBP5 methylation, while their progeny exhibited decreased FKBP5 methylation in comparison to controls (Figure 1).8 Methylation changes occurred at the same site for both the survivors and their children, suggesting that methylation in offspring is unique from first-hand exposure to trauma.8 However, conclusive evidence for the mechanisms that alter these epigenetic markers or transgenerational transmission from clinical studies is not yet available.8 Small sample sizes in these studies necessitate further investigation into epigenetic changes in a wider range of trauma-affected individuals.

Interventions 

If left untreated, trauma can induce long-term mental health problems, which can then be passed intergenerationally through social interactions between parents and their children, in addition to epigenetic mechanisms. In a study by Yehuda et al.,11 offspring of Holocaust survivors who did not talk about their traumatic experiences were found to suffer more with interpersonal relationships. This was likely due to Holocaust survivors attempting to avoid the grief associated with reliving their trauma, thereby causing distance with children and family members. Children of these distant parents might feel overwhelmed or responsible for their parent’s unresolved emotions, leading to their own mental turmoil.11 This finding suggests that social and environmental factors surrounding a child’s upbringing by trauma-exposed parents may further exacerbate epigenetic inheritance leading to psychiatric disorders. If cultural trauma is inherited purely genetically, little can be done to prevent symptoms of mental illness from arising. However, the additional social aspect of inherited trauma observed in this study suggests that when an individual understands and pursues treatment for their mental health problems, the benefit may be even greater than once thought. Further research is required to determine how and if children of individuals receiving treatment for their PTSD symptoms would be less likely to epigenetically inherit parental trauma than those left untreated. 

Conclusion 

The impact of trauma can remain a burden long after an individual experiences it. Although our findings acknowledge the interconnectedness between environmental exposures and epigenetic transgenerational inheritance of phenotype and disease, it is equally important to recognize that an individual does not need a familial connection to trauma in order to live with mental illness. Inheritance of epigenetic modifications resulting from an ancestor’s lived trauma can be identified as one potential biological underpinning of psychiatric disorders including PTSD; however, it is crucial not to reduce a person’s individual experiences down to a single inherited change in protein methylation. Although one cannot control whether they inherit or experience trauma, it is possible to prevent oneself from passing the trauma socially to their children by pursuing treatment. Studies need to be expanded to find methods of reverse methylating the MeCP2 protein, as well as observing what interventions can affect epigenetic inheritance of trauma. Society’s uninterrupted cycle of trauma and mental illness can now be better understood knowing that it can be inherited epigenetically, while continuing to consider physical, social, and environmental factors which may have additional effects.

FIGURE 1: Percent Methylation at FKBP5 intron 7, bins 1, 2, and 3 for Holocaust survivors and offspring. Red at (A) represents % methylation of FKBP5 in Holocaust survivors, while white at (A) represents % methylation in comparison subjects for each site, respectively. Red at (B) represents % methylation of FKBP5 in offspring of Holocaust survivors. White at (B) represents the % methylation in comparison subjects for each site, respectively. Methylation changes in both Holocaust survivors and their offspring display can be observed at site 6. 8

Reference List: 

1. Lehrner A, Yehuda R. Cultural trauma and epigenetic inheritance. Cambridge University Press. 2018;30(5): 1763-1777. Available from: doi:10.1017/S0954579418001153. 

2. Hinton DE, Good BJ. Culture and PTSD. University of Pennsylvania Press. 2015;1(16):3-49. Available from: doi:10.9783/9780812291469. 

3. Guerrero-Bosagna C, Skinner MK. Environmentally induced epigenetic transgenerational inheritance of phenotype and disease. Mol Cell Endocrinol. 2012;354(1-2):3-8. Available from: doi:10.1016/j.mce.2011.10.004. 

4. Kitcher P. The Lives to Come: The Genetic Revolution and Human Possibilities. 1st ed. New York: Simon and Schuster; 1997. 242 p. 

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6. Franklin TB, Russig H, Weiss IC, Gräff J, Linder N, Michalon A, et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry. 2010;68(5):408-415. Available from: doi:10.1016/j.biopsych.2010.05.036. 

7. Fyffe SL, Neul JL, Samaco RC, Chao HT, Ben-Shachar S, Moretti P, et al. Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron. 2008;59(6):947-958. Available from: doi:10.1016/j.neuron.2008.07.030. 

8. Yehuda R, Daskalakis NP, Bierer LM, Bader HN, Klengel T, Holsboer F, et al. Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation. Biol Psychiatry. 2016;80(5):372-80. Available from: doi:10.1016/j.biopsych.2015.08.005. 

9. Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Farrer LA, et al. Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacol. 2010;35(8):1684-92. Available from: doi:10.1038/npp.2010.37. 

10. Zannas AS, Wiechmann T, Gassen NC, Binder EB. Gene-Stress-Epigenetic Regulation of FKBP5: Clinical and Translational Implications. Neuropsychopharmacol. 2016;41(1):261-74. Available from: doi:10.1038/npp.2015.235.

11. Letzter-Pouw SE, Shrira A, Ben-Ezra M, Palgi Y. Trauma transmission through perceived parental burden among Holocaust surviors’ offspring and grandchildren. Psychol Trauma-US. 2014;6(4):420-429. Available from: doi:10.1037/a0033741. 

12. Perroud N, Rutembesa E, Paoloni-Giacobino A, Mutabaruka J, Mutesa L, Stenz L, et al. The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis. World J Biol Psychiatry. 2014;15(4):334-345. Available from: doi:10.3109/15622975.2013.866693. 

13. Watkeys OJ, Kremerskothen K, Quidé Y, Fullerton JM, Green MJ. Glucocorticoid receptor gene (NR3C1) DNA methylation in association with trauma, psychopathology, transcript expression, or genotypic variation: A systematic review. Neurosci Biobehav R. 2018;95:85-122. Available from: doi:10.1016/j.neubiorev.2018.08.017.

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