The genome in the making

Interview transcript

Books & Ideas: What is epigenetics? ?

Edith Heard: The word “ epigenetic » was introduced in 1942 by the embryologist, zoologist, philosopher and geneticist Conrad Waddington (1905-1975) to name a new science. Indeed, Waddington realized that it was necessary to link two disciplines: genetics on the one hand, and embryology, or developmental biology, on the other. These two worlds were separate and Waddington wanted to bridge these two disciplines by inventing the word “ epigenetic “.

For several years this word was not really used, neither by developmental biologists nor by geneticists. However, we realized in the 1970s, following the discovery ofDNAthat the shape of theDNA could be modified by methylation. Methylation is a chemical modification that can be attached to cytosine, one of the four bases ofDNA. The discovery of methylation then made scientists aware that there was a way to mark theDNA differently, that is to say, to change the way in which theDNA could be read, but without changing its sequence.

The word “ epigenetic » transformed little by little to ultimately describe the concept of a change in gene activity, or genome function, which can be inherited during cell divisions, or even across generations, but which does not does not affect the sequence of theDNA. So there was a shift in the use of the word in the 1970s and 1980s, linked to the work of people like Art Riggs and Robin Holliday.

More recently, the word has changed its meaning again: many people use it to simply refer to the link between genotype and phenotype. Any environmental change, these people believe, could trigger an epigenetic change. However, this definition poses a problem because we could speak more simply of gene regulation in this case. This recent use of the word is therefore still debated.

Books & Ideas: How the fate of cells can be determined from a single genome ?

Edith Heard: The question arose as to how, from a simple cell with the fertilized egg, we manage to have different cell types. In other words, how do we get from a simple fertilized egg to such complexity? ? We were thinking about XX^e century that this complexity was accompanied by a loss of genetic material, that is to say that we lostDNA as cell divisions progress, so that this or that cell can simply express part of its genetic material.

Studies by John Gurdon, Nobel Prize winner in 2012, refuted this idea by showing that if you take the nucleus and genetic material of a somatic cell and put it in the environment of the egg, you can then reprogram this nucleus to make it a whole individual. This is proof that a differentiated somatic cell contains the same genetic material as the fertilized egg: from this same genome we can create all cell types. There was therefore no loss of genetic material.

We have now understood that these are differential activities of genes, which occur in a very controlled manner and which allow cells to have a unique destiny. These changes in fate have a genetic origin but they must be fixed somewhere: for example so that a skin cell remains a skin cell. We therefore need mechanisms to freeze these decisions, that is to say so that an active gene remains active and so that an inactivated gene remains stably repressed during cell divisions. Epigenetics, as defined by Waddington then by Riggs and Holliday, plays a role in maintaining these states, so that cellular fate is maintained, even if with each generation it is reprogrammed.

Books & Ideas: What is the scientific significance of your discovery of the mechanisms of X chromosome inactivation in female mammals? ?

Edith Heard: Inactivation of the X chromosome is a process that occurs in female mammals, that is, in all individuals carrying both X chromosomes. The only chromosomes where there is a difference between males and females are indeed the sex chromosomes. The Y chromosome is quite small and carries few genes, although they are very important for male traits. The X chromosome is large and carries more than a thousand genes. Because of their size, a double dose of X chromosome in women is problematic: if both X chromosomes are fully expressed, the embryos die very early. It was therefore necessary that during development one of the two cell divisions. This X must remain inactive so that populations of cells, which express either the paternal X or the maternal X, arrive. This discovery of X chromosome inactivation was made more than fifty years ago.

What is interesting is that the two X chromosomes in a female embryo can be identical, for example in mice. However, in the same core one X will be active and the other off, and this state will be memorized. How to explain this ? The epigenetic model then plays its role par excellence since we find ourselves in the presence of a change in the activity of genes while theDNA is identical to him.

My team has been working on this process for a long time now. We observed in mice that at the time of fertilization both X’s are active then that the paternal X is inactivated at the four-cell stage. It is therefore always the paternal X which is inactivated at this stage although we thought that the inactivation occurred randomly. Then, at another point in embryogenesis, the paternal X is reactivated in the cells of the inner mass. Finally, after this stage, inactivation is random. These activation-reactivation phases that were discovered were quite unexpected. We thought we weren’t going back but we are going back. There is therefore a reprogramming of the epigenetic state and then a restoration. A few years later, there was the discovery by Shinya Yamanaka of the reprogramming of somatic cells into pluripotent stem cells. This is the equivalent of what we saw at work in the cells of the internal mass.

Books & Ideas: What are the links between epigenetics and cancer research? ?

Edith Heard: The idea that cancer was a disease of genetic alteration prevailed for a long time. However, it was gradually realized that it was more a matter of gene deregulation, where epigenetic processes would be involved. We can sequence genomes not only of normal cells but also of tumors. These are of course changes at the genome level, but there are also changes in gene expression in certain tumors which are not obviously linked to a change at the sequence level of theDNA. These are therefore indeed epigenetic changes.

The use of the epigenetic model in the study of cancer is booming. We realize that epigenetic factors can play an important role in tumors. There is also hope that we can turn back the clock with certain treatments. We could even treat patients to compensate for the aberrant repression of certain genes. Epigenetic changes are reversible, and so there is hope that they can be cured.

It was hope. In reality there are molecules of epigenetic actions which work in clinics and which can reverse certain types of leukemia. However, we do not yet really know at what level these molecules act. Scientists need to understand how these molecules really work and how these treatments work. In the future, there may be epigenetic treatments, combined with other treatments, to treat cancers at a very early stage and in a very targeted manner depending on the type of tumor and the type of individual affected.