It was in 2009 that the notion of epigenetics made sense to me, during a lecture by Patrick McGowan, invited to the Maison de Solenn by Professor Bruno Falissard (Centre de recherche en épidémiologie et santé des populations, or CESP). This specialist in neuroscience and epigenetics presented his study, published in the scientific journal Nature, showing that childhood traumas can modify the expression of certain genes and lead to suicide.
It was already known that alterations of the hypothalamic-pituitary axis (the hypothalamus and the pituitary gland are located in the heart of the brain), such as elevated levels of the stress hormone cortisol (a glucocorticoid), are associated with depressive episodes and suicide attempts .
To investigate a possible relationship with these tragic situations, McGowan studied the expression of a gene that codes for cortisol receptors (NR3C1) in the brain structure that contains the most cortisol: the hippocampus. This was done in three populations: victims of childhood suicide abuse (twelve people), suicide victims with no history of abuse (twelve people), and twelve controls (victims of sudden or accidental death, with no history of abuse).
He found that the expression of this gene was decreased only in victims of childhood abuse. And the mechanism involved was not genetic as such, with, for example, the mutation of a gene, but epigenetic. That is, one or several letters of the word that constitutes the gene were not changed, but were altered (like an e transformed into an é), in this case by methylation. The children could not cope with stressful situations due to the failure of this brain axis.
It is now known that the consumption of psychoactive substances can induce these epigenetic modifications. Identifying its mechanisms will help to better understand the prevention messages of "zero tolerance with alcohol and tobacco during pregnancy", which should also concern the future father.
Genetics-epigenetics: what are we talking about?
We are very aware of what characterizes our genetic heritage, our genome. Enclosed in the nucleus of cells, it extends along the chromosomes, made up of a protein-wrapped DNA molecule, the histones. This configuration of chromatin allows a large amount of genetic information to be placed in the tiny nucleus.
The genome itself is made up of coding (mainly genes) and non-coding regions. Information from the coding regions is only accessible to the cellular machinery if the chromatin is not too tightly coiled. In that case, the genes can be transcribed into as many messenger RNAs.
Each mRNA is driven out of the nucleus to be translated into a protein. Proteins are essential for a wide variety of functions within the cell and the organism, both structural and functional.
As mentioned, the text of a gene can have an error (mutation) in the DNA itself, which leads to the synthesis of an abnormal protein. This may be inconsequential, or it may lead to genetic diseases that are potentially transmissible to offspring.
But sometimes no mutation can be associated: you have to look not at the genetic text itself, but at what surrounds it.
The term epigenetics was first proposed by Conrad Hal Waddington, a British paleontologist and geneticist (1905-1975), in the 1940s, as "the branch of biology that studies the cause-and-effect relationships between genes and their products. ». He proposed the concept of epigenetic landscape, that is, the set of reversible, transmissible and adaptive modifications of gene expression without changing the text. This means that gene expression can be flexibly and dynamically reduced or inactivated throughout life.
The epigenome, or set of epigenetic modifications that a cell receives, thus constitutes a true memory of the environmental impacts (exposure to nutritional, toxic or psychosocial stresses) to which it has been exposed.
The main epigenetic mechanisms
Epigenetic modifications can occur at many levels and take many forms:
- Some small RNAs, RNAs that do not code for any gene, are called interfering because their function is to interfere with normal DNA expression. Therefore, they have a regulatory or structural role.
- Chromatin can be remodeled. This can lead to its inactivation and deregulation of gene expression.
- Histones, which allow DNA packaging, can also be chemically modified: by methylation (addition of a methyl group X-CH3), acetylation (addition of an acetyl group X-CO-CH3), phosphorylation (addition of a phosphate group ) or ubiquitinylation (addition of a small protein called ubiquitin, which controls the degradation of its target).
The effects are diverse (chromatin condensation or decompaction to repress or activate gene transcription, etc.), rapid and short-lived.
- Finally, DNA can also be modified by the same type of chemical reaction. For example, its local methylation deactivates the genes present, in a stable but potentially reversible way.
The epigenetic impact of tobacco
We had the opportunity to return to these great topics at the annual congress of the Société francophone de tobaccologie, in Reims, in November 2021. This was the topic of a session I led with Dr. Jean Perriot.
On this occasion, Johanna Lepeule (IAB, Grenoble) addressed the topic of maternal smoking and placental DNA methylation. In a study published in 2020 in BMC Medicine, she and her team analyzed the placenta of 568 women, divided into three groups: non-smokers (381 women); ex-smokers (70 women), who had stopped smoking in the three months before pregnancy and had not smoked during pregnancy; and smokers (117 women), who had smoked in the three months before and during pregnancy.
The main results were the following:
- Alterations were observed in 152 regions of the genome in which, after ex-smokers quit smoking, DNA methylation seemed to return to the same level as in non-smokers. Changes in these regions were classified as reversible.
- Alterations were observed in 26 genomic regions whose methylation level remained unchanged despite smoking cessation in former smokers, and comparable to that of smokers. Therefore, these regions carry the memory of preconception tobacco exposure.
Among the genes that are affected by smoking, some have been identified that are especially important for the development of the fetus and the baby.
The conclusion is, therefore, very clear: you have to stop smoking as soon as you plan to conceive.
Smoking cessation should involve both the mother-to-be and her partner. In fact, the DNA of developing sperm may also be affected by methylation.
The epigenetic impact of alcohol
In January 2022, the French National Academy of Medicine published a report on the subject, under the direction of Jean-Pierre Goullé and Michel Hamon (subcommittee on addictions), of which it is important to know several points. Here are the main ones, identified in animal models:
Cannabinoids: THC (Δ9-tetrahydrocannabinol) "is likely to cause epigenetic changes." They can be seen in a person whose parents used the drug before conception, or whose mother used it during pregnancy, or who was exposed to THC during adolescence or later. DNA methylation, histone modifications, and non-coding DNA modifications are observed.
Cocaine: Causes histone acetylation, DNA methylation, and non-coding DNA.
The consumption of legal (alcohol and tobacco) and illegal drugs modifies our epigenome. Therefore, it is important to take it into account in public health actions, particularly in young people and in couples who want to have children. The use of validated methods, based on psychosocial skills, already allows action in this direction.
Quoting Claude Olievenstein, a psychiatrist specialized in drug addiction: "Addiction is the confluence of a product (a psychoactive substance), an individual and an environment (family and sociocultural)". We have just seen how a psychoactive substance can affect our descendants and modify our genome in a reversible, transmissible and adaptive way. This encounter can make us more vulnerable and lead us to develop an addiction.
This article has been published in 'The Conversation'.