Epigenetics & metabolism

Mechanisms that are now called epigenetics allow the genome to modulate its function without modifying the information contained in the genes themselves.
The knowledge of these mechanisms showing a central role of metabolism makes possible not only to better understand the impact of the environment on cell function, but also to better understand diseases and to consider innovative therapeutic approaches.

Epigenetics: Non-genetic Information

In addition to the genetic code, there is a second level of information, less defined and more complex, which informs and controls gene activity more or less stably and possibly in a transmissible way to the next generation.
This information is essentially directly associated with either chemically modified DNA or the proteins that organize this DNA: the histones.

Histones allow the long chain of DNA to be packaged in a small volume that is the nucleus of eukaryotic organisms and also to store information underlying gene expression regulation.

The nature and degree of genes packaging determine their ability to be expressed or on the contrary to remain silent. The chemical modifications and the nature of histones bear information to modify the expression of the nearby or distant genes.

These chemical modifications have the peculiarity of being reversible: indeed some specific proteins, called enzymes, can implement or remove these modifications, thus establishing or modifying the instructions given to the genes and consequently modulating their expression.

These chemical modifications can therefore be considered as molecular markers recognized by machineries that control genes accessibility. A series of instructions allow the DNA to be buried in histones and not accessible. On the contrary, other instructions make genes visible to regulatory elements that are necessary to their expression.

New concepts: metabolism dictates epigenome

It is important to underline that enzymes involved in establishing chemical modifications of DNA and histones (and other regulatory proteins) almost exclusively and directly use molecules derived from cellular metabolism to achieve these changes. Enzymes that remove these modifications can be dependent on or sensitive to molecules produced by metabolism.
It can therefore be said that all so-called "epigenetic" enzymes link directly cellular metabolism to control of gene expression. In other words, these enzymes put in place information impacting more or less stably gene expression, which reflects the metabolic status of cells. Thus, the status of cellular metabolism largely determines instruction given to cellular machineries to express or not genes. Metabolism is therefore the master piece of the communication system between genome and environment: via the metabolism, changes in the environment can potentially impact gene expression status in a more or less long-term.
Schéma - Nouveaux concepts : le métabolisme dicte l’épigénome
How does the genome integrate information coming from its environment? Cell metabolism includes chemical reactions that synthesize or break molecules constituting the cell. Some compounds generated during these processes directly control chemical modifications of histones and DNA.  Thus they impact the functioning of genes and can contribute to leave a memory of a specific event at the genomic level. There is a continuous flow of matter between the environment, the metabolic processes and the epigenome. This flow adapts and adjusts the activity of the genome according to the status of the metabolism and thus indirectly of  the environment.

Anything that influences metabolism such as our diet, physical exercise or sedentary lifestyle, various pathologies and aging can affect how our genetic program works.

A significant number of experimental results using various models such as yeast, the plant Arabidopsis, the fly Drosophila, the worm C. elegans or mouse shows that a diet or simply experiencing stress or specific conditioning can influence the next generation without modifying their DNA. The precise mechanisms involved in this phenomenon are not yet fully understood. These models reinforce the example of organisms such as bee whose normal development and expressed phenotypes are fundamentally influenced by their food.


New applications: societal impact

Not only these discoveries reveal critical aspects of the regulation of cell and organisms life, but they also open up considerable areas of application in biotechnology and human health, as well as in more unexpected disciplines such as sociology.
The direct connection between epigenetic mechanisms influencing cell status and environment makes possible to identify environmental disruptions that can influence genes function and predict their effects. As far as pathologies are concerned, an in-depth understanding of these mechanisms would allow us to modify when desired gene expression status to take away the pathological and pathogenic status from cells and/or to make cells more receptive to targeted or generalized treatments.

Cell reprogramming presents several applications in the field of regenerative medicine and biotechnologies. The understanding of epigenetic mechanisms also makes cell reprogramming much more efficient and can therefore have a considerable impact in medicine, agriculture and related industries.

In addition, the pharmaceutical industry has realized that a new field of application is now opened to develop many new drugs. Indeed, because the epigenetic marks informing the genome are dependent on dozens of enzymatic activities, small molecules regulating these enzymes can change the nature of these instructions and thus modify gene expression. Other molecules can modify the recognition of these "marks" by cellular machineries and thus also modify the instructions given to genes.

The possibility of acting at different levels on gene expression with natural or synthetic molecules opens the prospect of new and numerous drugs capable of acting on a wide range of pathologies.

Regarding cancer, the first generations of so-called "epigenetic" drugs are already used clinically or are being tested on patients.

This knowledge of epigenetics also gives the fundamentals for good lifestyle practice and can improve general public health. Therefore it has a considerable societal and political impact.

Economically, the impact of this new knowledge is immense because pharmaceutical industry but also biotechnology and food industry are directly concerned.

In conclusion, by bringing the understanding of the interface between the metabolism and the genome, epigenetics is at the center of a revolution with considerable scientific, political and economic consequences.