Isabelle Mansuy, an epigeneticist at the University of Zurich, is no stranger to controversy. Since she first began studying epigenomic inheritance — the intergenerational transmission of factors like DNA methylation, histone modifications, and noncoding RNA that influence gene expression — more than a decade ago, she struggled with resistance from some researchers in the scientific community.

While epigenetic inheritance has been fairly well established in some invertebrates, including the nematode Caenorhabditis elegans, some researchers questioned whether this form of inheritance was possible in mammals due to extensive epigenetic reprogramming that occurs after the sperm fertilizes the egg (1,2).

Mansuy and other researchers found in their studies that mammals’ life experiences, including early life stress, diet, and exposure to endocrine disruptors, affected their offspring through mechanisms that did not appear to be behaviorally transmitted (3–5). Undaunted by their critics, researchers have been exploring potential mechanisms to determine whether epigenetics really are at play.

Their work is paying off. Earlier this year, a team at the Salk Institute for Biological Studies demonstrated that DNA methylation-edited mice passed down epigenetic edits for multiple generations (6). Mansuy’s work also suggested that RNA in sperm may be a major player in epigenetic inheritance (7). Now, Mansuy continues exploring the molecular mechanisms through which life experiences may be written into the germline and subsequently passed down through multiple generations.

How did you become interested in studying epigenetics and inheritance?

This research was launched by a consortium that I joined more than 20 years ago. The consortium brought together people to create an animal model of borderline personality disorder. At the time, the disease was not very well described, but we knew that it was a complex disease with a multitude of symptoms; many people with the disease had been exposed to traumatic experiences during childhood, often physical or sexual abuse.

Wherever we look, we see quite severe symptoms. 
- Isabelle Mansuy, University of Zurich

So, we decided to develop a protocol in mice that would model traumatic experiences in early life. After a couple of years, I thought, why not check the offspring and see whether they show any symptoms.

I had a hard time convincing my postdoctoral researcher to do the experiment, but it worked immediately. Our behavioral experiments on the offspring showed similar symptoms to those observed in male mice that were directly exposed to early life stress. Next, we wanted to understand the mechanism.

It took us many years to confirm that transmission happened through the germline. We needed to exclude social or behavioral transmission. For this purpose, using male mice was an advantage because they don’t contribute at all to raising the pups.

Our mice are isogenic, so they all have comparable genomes. When I see dramatic symptoms being transmitted, I automatically think of epigenetic factors. So that’s what prompted us to work on epigenetic inheritance.

What symptoms did you find in the offspring of the stressed mice?

There are multiple symptoms, including changes in behavior, metabolism, the immune system, and cardiac function. In terms of behavior, we see increased risk taking, which is visible across multiple generations. In the patriline, we see it until the fifth generation.

They also show depression-like symptoms, impaired memory and cognitive functions, and problems with social recognition; they can’t read social cues. In terms of metabolism, we see altered sugar and lipid metabolisms. Cardiac functions are impaired; the heart is hypertrophic. Wherever we look, we see quite severe symptoms. 

How are these epigenetic alterations transmitted?

In male germ cells, there are many elements of the epigenome that are altered by stress, including DNA methylation and noncoding RNA. These changes occur not only in sperm cells, but also in spermatogenic cells at earlier stages of spermatogenesis. We apply early trauma in mice, meaning that we induce trauma in pups that do not have sperm cells yet. But they do have spermatogonial stem cells, which produce sperm cells throughout life, so it could be a problem if those stem cells are affected. We wanted to find out if  spermatogonial stem cells are altered by trauma early in life, and if they still carry those epigenetic alterations in the adult. That is indeed the case. 

Is there any way to prevent the effects of trauma from being transmitted to the offspring?

In one study, we exposed male mice to trauma during the first few weeks of postnatal life and later exposed them to a diverse environment that includes social enrichment and the ability to exercise; it’s a lot of emotional stimulation. We saw that enrichment reversed the symptoms in these mice. Their offspring were protected from the effects of paternal trauma. We are doing the same experiment with female mice right now. 

Is it possible to determine if a trait is transmitted through parental epigenetics or parental behavior in humans?

It’s really hard to test in humans because we cannot exclude many factors, unlike in mice. In mice, we can do oocyte transfer, in vitro fertilization, artificial insemination, and cross fostering. In humans, researchers can’t separate people from their children for an experiment. There are some studies of people who were separated from their parents during war and so on, but confounding factors like stress are very important. 

Problems arise when people extrapolate and talk about causative factors in humans when it’s not at all causative; it’s only correlational. That can be misleading. These extrapolations and confounding factors and the fact that big conclusions have been drawn has really affected the field and has made people question the validity of the concept. 

What questions do you want to answer next?

One of the major things we've been working on for the past couple of years is understanding the mechanisms by which epigenetic factors are altered in germ cells. What is the link between exposure to stress and alterations in the epigenome in germ stem cells? We have done a lot of studies on blood since we see epigenetic alterations throughout the body, and one common factor that all body parts share is blood. 

Unlike the genome where there is one genetic code, the epigenetic code has multiple layers. 
- Isabelle Mansuy, University of Zurich

We hypothesized that blood itself probably carries signs of trauma, and that it is involved in both spreading the effects of trauma across the body and maintaining the aftermath of the trauma. Blood composition remains altered in the exposed individuals many months after the trauma; it’s also altered in the offspring, which have never been exposed to any trauma.

We showed that if we inject serum from mice exposed to trauma intravenously into control male mice that have never been traumatized twice a week for a month and then generate offspring, these offspring show some symptoms of trauma. This suggests that serum contains circulating signals that can reach the spermatogonia cells. Now, we need more work to identify the factors in the blood that are responsible.

This isn’t the whole story because not every symptom is recapitulated when we inject the serum. It’s mostly the metabolic phenotype, not the behavioral or cardiac phenotypes. This indicates that there are probably multiple factors. 

The epigenome is complicated. Unlike the genome where there is one genetic code, the epigenetic code has multiple layers, including DNA methylation, histone modifications, and noncoding RNA. The epigenome may vary from cell to cell or cell state to cell state. It’s not an all or none phenomenon.

This interview has been condensed and edited for clarity.

References

1. Frolows, N. & Ashe, A. Small RNAs and chromatin in the multigenerational epigenetic landscape of Caenorhabditis elegans. Philosophical Transactions of the Royal Society B: Biological Sciences  376, 20200112 (2021).
2. Xu, Q. & Xie, W. Epigenome in Early Mammalian Development: Inheritance, Reprogramming and Establishment. Trends in Cell Biology  28, 237–253 (2018).
3. Franklin, T. B. et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry  68, 408–415 (2010).
4. Watkins, A. J. et al. Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice. Proceedings of the National Academy of Sciences  115, 10064–10069 (2018).
5. Skinner, M. K. Epigenetic transgenerational inheritance. Nat Rev Endocrinol  12, 68–70 (2016).
6. Takahashi, Y. et al. Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice. Cell  186, 715-731.e19 (2023).
7. Gapp, K. et al. Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma. Mol Psychiatry  25, 2162–2174 (2020).