There is a lot of hope being held out for the field of epigenetics. Could it be the science that will establish the link between the social and the biological, behaviour and heredity? While epigenetics is an exciting discipline, we must remain vigilant.
Epigenetics is in vogue at the moment, but the word is not new. In 1942, Conrad Waddington suggested using it to describe the science that establishes the relationship between genotype and phenotype – that is, between the sequence of genes and the way they are expressed in the organism. For the British scientist and philosopher, he considered it to be a concept that mainly concerning embryonic development. His future work opened up the field.
Epigenetics is now defined as the transmission of stable, heritable traits that do not involve changes in the DNA sequence. It covers all systems of gene expression regulation. Two molecular mechanisms of epigenetics underlie the process: markers; chemical modifications of DNA that mark genes as active or inactive; and the organisation of the genome, that is, the way the DNA strand wraps around itself to allow the machinery that reads the sequence to access it – or not.
From metabolism to genetics
To understand the phenomenon, we can study two mice from the same lineage: one is brown, the other is yellow. This difference is not due to a sequence difference within a gene, but to the methylation of a gene. When the agouti gene is not methylated or only slightly methylated in melanocytes (skin cells), it is expressed and the mice are yellow. If the agouti gene is methylated, it is “switched off” by the molecular machinery, and it will not be expressed so the mice will be brown. More importantly, when we add folic acid to the diet of gestating mice, the proportion of yellow mice in the litters is reduced. As such, we now know that folic acid is essential for the synthesis of a methylation donor molecule. Epigenetics is therefore influenced by metabolic pathways and can respond to external signals, such as a particular change in diet.
Metabolism also influences the genome organisation via histones. These are DNA-associated proteins that organise DNA strand winding. They compact the DNA molecule 10,000 times and allow it to be confined in the cell nucleus. They also regulate the expression of the genome: compacted regions cannot be read and the genes concerned are considered to be deactivated. To bind to DNA, which is negatively charged, histones are positively charged. A chemical modification – known as acetylation – changes their overall charge and reduces their affinity for DNA. A molecule produced by the breakdown of sugars and lipids is required for this reaction, thereby providing another molecular link between metabolism and gene expression.
Is it simply enough then to change one’s diet to change the expression profile of one’s genome? No, for most people the effects of such changes on gene regulation are minor. That said, the embryo is particularly sensitive to epigenetic changes and a metabolic signal can significantly affect development.
Many open questions
Experiments on gestating mice show that environmental factors, such as stress, exposure to toxic compounds or diet, can have an impact on the epigenetic markers of the offspring. Is this also the case in humans? It is not possible to lock people up to control their environment, but we can get around this by studying the impact of a major stress on a population. When researchers at the University of Leiden studied people who had lived through the great famine of 1944 in the Netherlands, they identified a particular type of methylation in their children. Some thought this was evidence of human epigenetic inheritance. However, this observation is not proof of a causal link and the demonstration of a mechanism for transgenerational transfer of marks is still lacking in humans. Indeed, epigenetic marks are reprogrammed during gamete maturation. They therefore do not appear to be transmissible to future generations.
Another idea that is mistakenly considered proven is the link between biology and behaviour. In this field, researchers often study identical twins. These are two individuals with identical or nearly identical genomes, for whom differences over time are often attributed to the influence of environment, lifestyle and experience in the broad sense. A perfect model for epigenetics? No. It is difficult to distinguish biological facts from behaviour. For example, if a child suffered abuse as a child and his or her descendants are also victims. Is there a molecular or cultural mechanism that needs to be addressed here? Disciplines at the boundary between social science and biology are tackling these questions, but sometimes they draw hasty conclusions.
Finally, the fact that the field is becoming popular can be explained by the reversible nature of epigenetic marks. While it is at present difficult to modify the genome using gene therapies, the idea that treatments, called “epidrugs”, can modify a pathological phenotype by acting on epigenetic marks is attractive. This is particularly the case for cancer, where the combination of genetic and epigenetic changes alters the identity of the cell and underpins tumour behaviour.
Pharmaceutical companies are developing inhibitors to modify epigenetic marks. But, it is difficult to target the marks responsible for pathological phenomena without altering healthy marks. Pathological or not, they have the same chemical nature. Researchers are developing molecular biology techniques to try and resolve this issue, but clinical proof is still lacking.
All this research shows just how active the field of epigenetic research is. It also points to a shift in thinking in biology, in which plasticity replaces the idea of determinism. We can thus look forward to change with optimism, and explore how education and modifications in behaviour can have a positive impact on the future of individuals.