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How cells remember (and sometimes struggle to forget)

The twentieth century has been a great period for Biology thanks to the discovery of its star molecule: the DNA. That huge double helix structure has been proven to be the location of the genetic information in the cell, the unit of life. It contains indeed thousands of "genes" which are all "recipes" for the creation of its functional tools: the proteins. Proteins structure the cell, form their wall, allow them to live, grow, divide and to perform their task within the organism.

From each of the 20 000 genes of the human being, one or several types of proteins can be produced. All these genes are part of the genome; and therefore, knowing the genome is enough to describe everything that the cell contains. By extension, since all the cells of our body contain the same DNA, the genome also defines all the content of our body.

From there, a question naturally arises; and scientists were quick to ask it: if knowing the genome is sufficient to fully describe what the cell contains and since the same genome is shared throughout the organism, how do we explain that two cells of the same organism can be different? Indeed, various organs compose us, and one just has to look in a microscope to realize that the cells of the liver differ from the cells of the heart. The idea of the cell that we used to hold needed an update: it was clearly not just the result of a blind and direct execution of the genome’s instructions.

Illustration by Renaud Helbig.

How can different traits be obtained from the same genetic information? How different dishes can be obtained from the same recipes? If the genome is indeed the same in both cells, it is not expressed in the same way: a set of supplementary information will guide the cell, telling it which genes to consider in order to function. This annotation mechanism for the DNA is called epigenetics: what is above the genetics.

How does it work?

Epigenetics is the study of all external influences that lead to a modification in the expression of the genetic information in the cell. This influence can come from surrounding cells or from the outside environment. It does not change the genes themselves: it simply controls their expression. For instance, an hormone spotted by the cell sensors can prevent or promote the production of some genes. During this cellular "reprogramming", it is not the DNA molecule itself that is modified, but rather the way it is structured: chemical compounds can induce structural modifications in a region of the DNA (see box); consequently genes therein will not be accessible by the cellular machinery. Therefore, these genes will still be there, but, silenced, they will not be expressible as proteins any more.


Epigenetic modifications

A chromosome is composed of very long DNA molecule which wraps around big structures, the histones. On the DNA, there are coding sequences, the genes, that may be expressed as proteins. An external compound, coming from the surrounding cells or from the environment, may cause epigenetic changes for example by:


As external stimuli shape the DNA structure, the set of expressible genes in the cell is thereby refined. In the end, the native genetic information – the genome – will be modulated by the accumulated epigenetic information – the epigenome. An important feature of the epigenome is its heritability: when the DNA replicates for a division of a cell, the epigenetic annotations are copied in the same way. Therefore, all cells from one lineage will inherit in turn the epigenetics traits from their ancestral cells.

This feature of epigenetic differentiation is the key mechanism of tissue differentiation. The main phase during which epigenetic information is acquired takes place during the gestation of the embryo. Initially, the cells of the embryo are stem cells, that is to say undifferentiated from their neighbours. Then, a chemical signal that comes from outside the cell causes an epigenetic modification that causes it to specialize. The cells that will arise from its division will inherit these first adjustments and will go through other changes that will lead them to become cells of the skin, the intestine, the muscles, or of any other organ.

Health issues

The study of epigenetics only really took off in the 90s. It allowed a better understanding of some cellular mechanisms, and also it appeared that it is linked with many diseases, in the same manner as genetics. Some congenital disorders may indeed be the result of a detrimental epigenetic modification during pregnancy. It has been proven by studying pairs of identical twins, that, therefore, have exactly the same genome. One child may contract the Beckwith-Wiedemann syndrome (causing an excessive growth of the foetus), while its sibling remains healthy. It has been shown that, during embryonic development, the first one must have gone through an epigenetic error that lead to a wrong expression of the gene IGF-2, involved in the growth of the organism.

In the same way that researchers looked for genotoxic substances (that cause mutations on the DNA), several studies were conducted to find the influence that some chemicals could have on the epigenome. It has been revealed that it was the case of endocrine disruptors such as Bisphenol A and dichlorodiphenyltrichloroethane (DDT); these molecules, used in the industry or as pesticides, mimic the behaviour of true hormones. The exposure to these substances, especially during embryogenesis, disrupts the process of sexual differentiation. These studies helped to initiate legislative changes: following early studies, DDT has been forbidden, or highly restricted, since the 80s in many countries (European Union, USA, Canada, Mexico etc.); and more recently in the 2000s, the use of Bisphenol-A in the fabrication of baby bottles has been forbidden by the European Union and Canada.

Also, cancers proved to be closely linked to epigenetic defects. Looking at cancer cells, it appears that the DNA molecule has undergone many mutations, but also that the epigenome has been completely altered. It is nevertheless unclear whether epigenetic modifications are the cause or the consequence of the cancer.

Other studies showed that many diseases or pathologies were linked to epigenetic modifications: obesity, diabetes, infertility or cardiovascular diseases. However, if correlations between epigenetics and these disorders has been established, cause-and-effect links are not easy to obtain. Is the sickness the cause of the epigenetic change? Is it a deleterious consequence? Or do both come from another phenomena? The epigenetic modification could even be a response of the organism to the disorder and not one of its harmful effects. Conclusions are not easy to draw and are still largely debated in the scientific community.

Trans-generational?

One final question definitely arouses the interest of scientists and more broadly of the public: are epigenetic modifications heritable, not only from cell to cell, but also from parent to children? Is the epigenome, which has been constituted in interaction with environment all our life long, transmissible to our offspring? Can epigenetic alterations possibly linked to obesity end up in our offspring as a bad heritage of our lifestyle?

As for mammals, that seems to be rather complicated at first glance. Indeed, during the first embryogenesis phases, the DNA undergoes a "reset" of the epigenetic information. The genome is purified from the old epigenetic influences and is ready to create again a new being solely from the newly formed gene pool.

Nevertheless, almost 1% of the genes do not undergo this reset: they are called imprinted genes. A gene of this kind will continue to carry the epigenetic imprint of its parents, and, by this mean, it may transmit erroneous epigenetic modifications. In mice, some transgenerational effects have been detected, concerning obesity for instance. For Homo sapiens, many studies have been conducted, describing correlations across several generations. For example, children of Dutch mothers who suffered starvation while pregnant during the winter 1944-45 show some particular epigenetic alterations 60 years later. But here again, conclusions are still debated among the scientific community. After all, the children themselves suffered from starvation when they were in utero and the modification may be a direct effect of the environment rather than a transmission from the mother's epigenetic heritage. On a larger scale, the other studies are not always considering the fact that the parent and the child live in the same environment: the fact that they breath the same air or have the same diet might also be a good explanation for their similar epigenetic profile. Similarly, mutations on the genome are not always considered as a possible hypothesis to explain these hereditary effects.

Conclusion

Studies on epigenetics reflect pretty well the current tends in Biology. Like genetics, it gives to the theorists a framework in which old questions can find new answers: epigenetics help explain cell differentiation and the organisation of the multicellular beings that we are. Like genetics, it raises issues in terms of public health: it questions the use of some substances that induce perturbations in our cells. Like genetics, it also raises questions about the innate and acquired parts in our life.

To my mind, they also share some flaws. The enthusiasm for these topics leads to many studies from which hasty conclusions are drawn and exposed to the public: many newspapers headline about the discovery of the gene of autism, the gene of schizophrenia or the gene of depression; definitive truths about epigenetic transmission of obesity and diabetes to one's children are already drawn. Even if they are properly done, the studies are not free of criticisms which are inherent in research: correlation is no causation; a result for mice is not necessarily transposable to humans; if some epigenetic effect is proved, it may still be insignificant compared to genetics. Both epigenetics and genetics are relatively recent and researchers, popularizers and the public should remain cautious in their conclusions.

Bibliography

  • Deborah, D. (2012). Epigénétique et environnement. [Video available on youtube, French]. A conference of Institut Curie about epigenetics. It shows the debates in the scientific community about the studies on epigenetics.
  • Skinner, M.K., Manikkam, M., and Guerrero-Bosagna, C. (2010). Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab 21, 214–222. Review about the environmental influence on epigenetics.
  • Baccarelli, A., and Bollati, V. (2009). Epigenetics and environmental chemicals. Curr Opin Pediatr 21, 243–251. A review about the effects of chemicals en epigenomes.
  • Heijmans, B.T., Tobi, E.W., Stein, A.D., Putter, H., Blauw, G.J., Susser, E.S., Slagboom, P.E., and Lumey, L.H. (2008). Persistent epigenetic differences associated with prenatal exposure to famine in humans. PNAS 105, 17046–17049. The article describing the transgenerational effects of winter 1944-45 starvation on Dutch pregnant women.