Neglect, calamitous events or even abuse: traumatic childhood experiences increase the risk of mental and physical illness and can lead to psychiatric disorders later in life. But how do stressful events early in life persistently affect brain functions? What happens in a child’s nerve cells when fear and stress overwhelm their normal coping mechanisms?
“Today, we believe that experiences are stored as a result of changes in the connections between brain cells. But what happens exactly at the molecular level in these cells remains a mystery,” explains ETH Fellow Rodrigo Arzate-Mejia, who has spent most of the last twelve months conducting research in the neuroepigenetics laboratory headed by Isabelle Mansuy – a professor both at ETH Zurich and the University of Zurich.
More than the sum of our genes
With the advent of genetics, the view that our genes determine who we are has dominated biology for decades. However, new knowledge gained from the sequencing of the genome has made clear that this view is too rigid. For young biologists like Arzate-Mejia, who we talked to virtually due to coronavirus restrictions, the genetic determinism of the 1990s is no longer tenable: “There is now solid evidence that environmental factors such as the social milieu we live in, our diet or physical exercise affect both our genome and the activity of our genes.”
The way these external factors act on our genome is by modulating the epigenome, which is an ensemble of biochemical marks on or around our DNA. Unlike DNA, whose sequence is fixed, it can be modified by a changing environment. Epigenetic mechanisms are necessary to read and interpret DNA. “Without them,” explains the ETH postdoc, “genes are nothing more than a raw code. Just like a score without a musician to interpret it.”
The modification of the epigenome by the environment is one way to explain why identical twins – who share the same genetic material – can differ both physically and in character. Depending on their life experiences and living conditions, they can exhibit slight differences in the level and timing of the activity of some of their genes, which accumulate over time and progressively change their features.
Strikingly, the environment can also modify the epigenome of germ cells. In recent years, Mansuy and her team have showed in mice that living conditions can leave epigenetic traces in our genes that can be passed from one generation to the next through germ cells. For example, depressive behaviour due to childhood trauma can be inherited just as much as eye colour or physical stature.
Arzate-Mejia was 16 when he first heard about epigenetics. After coming second place in the National Biology Olympiad, organised by the Mexican Academy of Sciences and aimed at contributing to the advancement of talented secondary school students, he attended a lecture on molecular genetics. The subject has fascinated him ever since. “That was the first time I heard that all cells contain the same DNA, albeit with very different functions as a result of divergent epigenetic mechanisms and interaction with their environment.”
The question of how genes are regulated fascinated him throughout his studies at Universidad Nacional Autónoma de México in Mexico City. After research visits at Johns Hopkins University, the Marine Biological Laboratory in Massachusetts and Emory University, Arzate-Mejia completed his doctorate in 2020. For his dissertation, he applied a variety of innovative methods from the fields of molecular biology, genetics and bioinformatics to demonstrate the crucial role played by genomic architecture in the regulation of genome activity.
A cell’s DNA is around two metres long. Although it is packed in the nucleus, it still has room inside this tiny space to change its structure. How and which genes are active thus depends on the spatial arrangement of the DNA in the nucleus. Moreover, the DNA can form loops that allow some genes from other parts of the genome to be isolated in chromatin loops. “Since some genes are very important and must be tightly controlled, they are given their own space in the cell nucleus within these loops,” explains the ETH postdoc. In recognition of his findings, Arzate-Mejia was awarded the Weizmann Prize for the best dissertation in the natural sciences by the Mexican Academy of Sciences. The dissertation was also published in the scientific journal Nature Communications.
The molecular basis of traumatic experiences
After completing his doctoral studies, Arzate-Mejia decided to specialise in neuroepigenetics. He is fascinated by nerve cells: “Unlike other cells, neurons do not undergo further cell division. They integrate a great deal of information, adapt continuously to their environment and are therefore useful for studying how experiences are stored at the molecular level.” Research into epigenetic changes in the brain is also only in its infancy. For Arzate-Mejia, it is an ideal research field for expanding his knowledge of genomic architecture to encompass the area of cognitive processes.
It was a stroke of luck for Arzate-Mejia that a postdoc position opened up in 2019 with Isabelle Mansuy, a pioneer in this field: “I couldn’t have hoped for a better place to work on my current research,” he emphasises. His move to Zurich was delayed due to the coronavirus pandemic but otherwise went smoothly thanks to the efforts of everyone involved.
Traumatised nerve cells
To understand how traumatic experiences affect neurons, Arzate-Mejia works with laboratory mice, which are particularly suitable as model organisms and provide insights that are applicable to humans.
Arzate-Mejia explains the experimental set-up: “We subject mice to conditions that simulate childhood trauma in humans. Once the animals become adults, we test their behaviour and cognitive performance and study their brain cells in search of any persistent epigenetic changes.” He insists that the experiments on animals are conducted with great care and in extremely strict and regulated conditions, and subject to completion of compulsory courses. “Without animals, research into the consequences of trauma would not be possible. We treat them with the utmost respect.”
Initial research results suggest that those genes that play a key role in cognitive functions are indeed protected by chromatin loops in brain cells. Any changes in the DNA structure brought about by stress that compromise this protection could alter the activity of these genes by making them interact non-specifically with their genomic surroundings. For the ETH postdoc, these findings are very promising: “Although my work is still at an early stage, I believe that this mechanism will provide us with a better understanding of how traumatic experiences leave their mark on brain cells.”