An epigenetic legacy of the Holocaust?

The legacy of the Holocaust is an emotive subject, and the recent paper by Rachel Yehuda and colleagues claiming that epigenetic changes linked to trauma experienced by Holocaust survivors can induce similar changes in their children has received a lot of media attention (also reported in this edition of BioNews). The primary lesson I took from this interesting paper is that human studies of transgenerational responses (as I like to call them) are fraught with difficulties, but definitely worth pursuing. 

Human observations do suggest, in line with animal experiments, that parental or ancestral experience may influence offspring development and health. The impact of Holocaust survival on the next generation has been investigated for years. The challenge has been to show that the observed transgenerational effects are not just down to cultural transmission through altered parenting, for example, or due to a regular genetic predisposition to anxiety and depression. If there is, indeed, a new aspect of biological inheritance that transmits the effects of parental or ancestral early-life experience to the next generation, then what is the molecular mechanism?

One possibility is an induced epigenetic change in the Holocaust survivor that is transmitted by the eggs or sperm to then influence development of their offspring. Epigenetics refers to enduring (but ultimately reversible) changes in the pattern of gene activity, during embryo development and beyond, that do not involve alteration of the DNA sequence. One form of epigenetic regulation is to add methyl (CH3) groups to the DNA at particular sites in the genome that, in turn, alter the (nearby) gene activity. Thus DNA methylation is an added layer of information beyond the DNA sequence variation — gene variants — you inherit from your parents.

In their study of 32 Holocaust survivors and 22 of their adult offspring, Yehuda et al focussed on the gene encoding the FK506-binding-protein 5, called FKBP5 for short. They did this for good reason, because FKBP5 activity helps regulate glucocorticoid hormone balance, which is disturbed in stress-related psychiatric disorders like post-traumatic stress disorder (PTSD). Furthermore PTSD — that has been shown in earlier studies to be increased in Holocaust survivors and their offspring — is associated with changes in the activity of the FKBP5 gene.

The paper's main finding is that Holocaust survival is associated with higher methylation at a relevant site within the FKBP5 gene compared with a small control group. In keeping with some possible transgenerational effect, the same site in the FKBP5 gene also shows methylation changes in the offspring generation. However the offspring have lower methylation levels compared to controls. This direction difference between Holocaust survivors and their offspring 'was unexpected' the authors say. Well perhaps it should not have been that unexpected. The authors had previously shown such a direction difference between generations in the activity of an enzyme that is also involved in moderating glucocorticoid action.

What can we make of these FKBP5 gene methylation findings in Holocaust survivors and their offspring? The sample sizes were small, particularly the control sample of eight parents and nine offspring from Jewish families living outside Europe during World War Two, so the results must be considered preliminary. This study does not address the nature of the actual signal between generations. However, the direction difference in FKBP5 gene methylation between exposed parent and their offspring reminds us that we should not expect transgenerational responses to be just Lamarckian 'inheritance of acquired characteristics' or the underlying mechanism to be just inheritance of acquired epigenetic changes. It is going to be much more complicated.

The authors say their findings 'may reflect intergenerational biological accommodation'; in other words, may be an adaptation. In general, we might expect some types of response to a challenge to be an adjustment that protects us and restores effective function, whilst other responses may be submission in the face of overwhelming forces. Both responses could have survival value. The majority of Holocaust-exposed parents in the present study were women and it may be that their chronically raised cortisol level results in their developing fetus adopting a different glucocorticoid hormone balance point, and the observed lower methylation of the FKBP5 gene is connected to this. Perhaps the simplest conclusion to make is that transgenerational responses will turn out to be very complicated interactions between experience, genetics and epigenetics. By all means 'watch this space', but it will be for years to come.