Researchers at Tel Aviv University have discovered three rules that dictate epigenetic inheritance – meaning transgenerational inheritance through means other than changes in DNA sequences. Published today in the leading scientific journal Cell, the study was led by Prof. Oded Rechavi and his research student Dr. Leah Houri-Zeevi of the Department of Neurobiology at the Faculty of Life Sciences and the Sagol School of Neuroscience at Tel Aviv University.

Most experiences we acquire in our lifetime will not be passed on to our descendants. For example, our workout in the gym today will not make our children stronger. However, studies conducted in recent years on epigenetic inheritance in worms challenge our traditional concepts regarding the limits of inheritance and evolution, indicating that some acquired traits are in fact passed on to subsequent generations. Prof. Rechavi explains: “Epigenetic inheritance of responses to the environment occurs independently of changes to the DNA sequence, through other inherited molecules. In many organisms, responses to environmental changes, such as stress, involve small RNA molecules that silence or block the expression of certain genes.” In recent years, research on C. elegans worms – an important and widely used model animal – has shown that small RNA molecules can be transmitted to subsequent generations, thereby passing on certain traits.

In previous research projects, Prof. Rechavi discovered that worms transfer to their offspring small RNA molecules containing information on the parent’s environment, such as viral infections, nutrition, and even brain activity, thereby contributing to the survival of subsequent generations. In the current study, Prof. Rechavi and his team tried to understand whether transgenerational epigenetic inheritance via small RNA molecules is governed by specific rules, or alternately, occurs passively and randomly.

According to Prof. Rechavi, “C. elegans is the preferred model organism for research on transgenerational epigenetic inheritance, for several  reasons: Its generation time is three and a half days, allowing us to study many generations in a short period of time; every worm produces hundreds of descendants, providing strong statistical validity; environmental exposure can be fully controlled; and each worm fertilizes itself, so that differences in DNA are almost completely neutralized.”

Dr. Houri-Zeevi explains that “Many laboratories have noted that at the level of a population epigenetic inheritance through small RNA endures for about three to five generations in worms. In a previous study, we discovered a mechanism that controls the duration of the inheritance, proving, in effect, that this type of inheritance is a regulated process. But still the question remains: Why are some worms strongly affected by their ancestor’s environmental responses, while others do not inherit the epigenetic effect at all – despite the fact that all offspring are almost identical genetically. This partial inheritance has been known for some time, but how epigenetic material is distributed among the offspring remained a mystery. We wanted to find out whether there was any pattern in the inheritance, that might explain and allow us to predict who would inherit the epigenetic features – and for how long.”

The researchers used a genetically engineered worm carrying a gene that produces a fluorescent protein – making the worm itself glow under fluorescent light. The researchers then initiated a heritable small RNA silencing response against the fluorescent gene and observed which descendants had inherited the silencing response and stopped glowing, and which descendants ‘forgot’ the parental response and started expressing the fluorescent gene once again after several generations. Dr. Houri-Zeevi repeated this process over and over again, in an attempt to understand the rules governing the epigenetic effect. Altogether she examined dozens of worms lineages, including more than 20,000 individual worms. But the most challenging part, according to Prof. Rechavi, was deciphering the different inheritance patterns and understanding the rules behind them.

Ultimately, through in-depth investigation of the inheritance mechanism, the researchers discovered three laws that can explain and even enable the prediction of who inherits the epigenetic information:

• First law: Inheritance is uniform in worms descending from the same mother – namely worms of the same lineage. The researchers were surprised to learn that differences in inheritance observed in previous studies were in fact ‘concealed’ due to the method of examining whole worm populations rather than distinct lineages.
• Second law: Inheritance is very different in worms derived from different mothers, even though the mothers themselves are supposedly identical, because the worm fertilizes itself. The researchers characterized the mechanism that creates the differences between mothers who are genetically identical and found that differences between descendants stem from varying ‘internal states’ randomly adopted by the mothers. Essentially, the mother’s internal state, the level of activity of the inheritance mechanism in each mother, determines the duration of inheritance, and thus the fate of subsequent generations.
• Third law: The longer the duration of the epigenetic inheritance – namely, the greater the number of generations in a specific lineage who inherits the trait – the greater the probability that it will continue on to the next generation as well, “in something like transgenerational momentum, resembling the ‘Hot Hand’ rule in basketball.”

According to Prof. Rechavi, we do not yet know whether the exact same transgenerational epigenetic inheritance mechanism exists in humans as well: “We hope that the mechanism we have discovered exists in other organisms as well, but we’ll just have to be patient. We must remember that genetic research also began with Friar Gregor Mendel’s observations in peas, and today we use Mendel’s laws to predict whether our children will have smooth or curly hair.”

“The idea of acquired traits passed on to descendants is as old as it is outrageous. Even before Darwin and Lamarck, the ancient Greeks argued about it, and it seems to be incompatible with genetic inheritance through DNA,” adds Prof. Rechavi. “The worms changed the rules by showing us that inheritance outside the genetic sequence does exist, via small RNA molecules, enabling parents to prepare their offspring for the difficulties they have encountered in their lifetime. From one study to the next we shed light on the molecular mechanisms and mysterious dynamics of epigenetic inheritance, with the present study providing laws and introducing some ‘order into the chaos’.”

A new Tel Aviv University study examined the brain’s reactions in conditions of uncertainty and stressful conflict in an environment of risks and opportunities. The researchers identified the areas of the brain responsible for the delicate balance between desiring gain and avoiding potential loss along the way.

The study was led by Tel Aviv University researchers Prof. Talma Hendler, Prof. Itzhak Fried, Dr. Tomer Gazit, and Dr. Tal Gonen from the Sackler Faculty of Medicine, the School of Psychological Sciences and the Sagol School of Neuroscience, along with researchers from the the Tel Aviv Sourasky Medical Center (Ichilov) and the University of California, Los Angeles School of Medicine. The study was published in July 2020 in the prestigious journal Nature Communications.

Prof. Hendler explains that in order to detect reactions in the depths of the brain, the study was performed among a unique population of epilepsy patients who had electrodes inserted into their brains for testing prior to surgery to remove the area of the brain causing epileptic seizures. Patients were asked to play a computer game that included risks and opportunities, and the electrodes allowed the researchers to record, with a high level of accuracy, neural activity in different areas of the brain associated with decision-making, emotion and memory.

Your brain suggests – play it safe

Throughout the game, the researchers recorded the electrical activity in the subjects’ nerve cells immediately after they won or lost money. The subjects were asked to try to collect coins while taking the risk of losing money from their pool. It was found that the neurons in the area of ​​the inner prefrontal cortex responded much more to loss (punishment) than to the gaining (reward) of coins.

Moreover, the researchers found that the avoidance of risk-taking in the players’ next move was affected mainly by post-loss activity in the area of the hippocampus, which is associated with learning and memory, but also with anxiety. This finding demonstrates the close relationship between memory processes and decision-making when risk is present (stressful situations). That is, the loss is encoded in the hippocampus (the region of the brain associated with ​​memory), and the participant operating in a high-risk stressful situation preferred to be cautious and avoid winning the coins (forfeiting the gain).

The experience of winning, however, was not encoded in the memory in a way that influenced the choice of future behavior in conditions of uncertainty. An interesting point is that this phenomenon was found only when the subject was the once influencing the result of the game, and only in the presence of a high risk in the next move, which indicates a possible connection to anxiety.

Prof. Hendler summarizes: “Throughout life, we ​​learn to balance the fear of risking loss with the pursuit of profit, and we learn what is a reasonable risk to take in relation to the gain based on previous experiences. The balance between these two tendencies is a personality trait but is also affected by stress (like the current pandemic). A disorder in this trait increase sensitivity to stress and can cause non-adaptive behavior such as a high propensity for risk-taking or excessive avoidance.

“Our research shows for the first time how the human brain is affected by the experience of failure or loss when it is our responsibility, and how this inclination produces avoidance behavior under particularly stressful uncertainty. An understanding of the neural mechanism involved may guide future neuropsychiatric therapies for disorders featuring excessive avoidance, such as depression, anxiety, and PTSD, or disorders associated with excessive risk-taking, such as addiction and mania.”

Featured image: Prof. Talma Hendler