Editing the epigenome

DNA is a molecule that contains all the hereditary material of an organism. Intriguingly, even though all our cells contain the same genome (the total of all genes), there are many different cell types, such as muscle cells and nerve cells. Cells gain their particular identity and functionality because some genes are switched on, and others are permanently switched off. For example, the gene coding for myosin is 'on' in muscle cells. As a result, this cell type produces the myosin protein. Myosin helps to contract muscle fibers. Nerve cells do not need to contract, so the gene for myosin is not switched on in nerve cells. The epigenome is instructing which genes should be switched on or off in each specific cell type. Therefore, epigenetics is referred to as the operating system of our genome. The epigenome acts as an instructing layer of the DNA opening-up the genome in regions where genes are switched on and compacting the genome in those regions where genes are kept off.

The epigenome acts as a molecular 'dimmer'; chemical modifications such as DNA methylation, determine whether, and how much, genes are turned 'on' or 'off'. These dimmers are thus important in regulating the final amount of protein produced in each cell type. This is essential as it ensures the proper functioning of body processes. Epigenetic chemical reactions are reversible and give the epigenome its flexibility to adapt the activity of genes to environmental conditions and thereby the functioning of cells and tissues.

Why is knowledge about the epigenome important? When the operating system of the genome (the epigenome) is disrupted, it can lead to dysregulated body processes. In some cases this can lead to diseases, depending on which genes are epigenetically disrupted. Studying how the epigenome regulates genes may thus not only contribute to knowledge about the functioning of genes and cells, but also provides information about health and the cause and course of medical conditions.

Epigenetic drugs are able to adjust the chemical epigenetic composition and can correct dysregulated body processes. Some epigenetic drugs have already reached the market. These epi-drugs are in general rather toxic as they do not act gene specific. Therefore, scientists are studying innovative technologies that can gene specifically reprogramme the epigenome. This can be attained by epigenetically switching genes on or off.

In agriculture, too, scientists are looking for ways to influence properties of crops that are of interest to farmers, like the flowering time of plants or the time of fruit ripening. These properties can be modified by genetically altering the DNA of seed, but also by making changes to the epigenome. In this manner, yield or resistance to stress caused by drought can for example be improved.

In the lab it is already possible to effectively reprogram the epigenome at specific sites in cells and animals, thereby altering specific body processes. However, whether these changes are long-lasting is still unpredictable. Precise, predictable, and long- term epigenetic editing is essential to use regulating the epigenome as medical and biotechnological application. To this end, the scientists of the Epi-Guide-Edit consortium will focus for the next five years on predicting the rules for long-term (but reversible) modulation of the epigenome. To this end, the researchers will use the CRISPR-Cas system

The Epi-Guide-Edit consortium is seeking to understand which factors determine why the epigenetic code of some genes allow for long-term epigenetic changes when edited, and others not. Scientists in the consortium will also determine which enzymes are most effective to edit the epigenome. These findings will provide key instructions for editing the epigenome. Epi-Guide-Edit scientists will test these instructions in both mammalian and plant cells, to confirm their universal functionality across species. This information is a crucial step towards developing epigenetic editing into a Key Technology to apply in practice.

Editing the epigenome (epigenetic reprogramming) is different from editing (or modifying) the DNA building blocks. Insertions or deletions of the DNA are genetic modifications. In contrast, when scientists edit the epigenome, the building blocks of the DNA are not altered but the epigenetic control of a gene is changed. Epigenetic editing enables researchers to differently instruct genes (to be switched on or off), leaving the genetic material intact.

Any new technology that potentially leads to a groundbreaking innovation, creates uncertainty and controversy. Especially when it affects living organisms. This will be no different for the innovative epigenetic editing technology. Currently, there is, for example, still uncertainty about technical aspects as well as the regulatory framework. To develop technologies in a responsible way, it is necessary to anticipate also on potentially unintended negative consequences of the technology. And it is important to reflect on explicit and implicit assumptions that underlie research projects. In the Epi-Guide-Edit research project, it is assumed that citizens embrace the opportunities of epigenetically editing because there will be no genetic modifications involved.

One of the questions that the Rathenau Instituut will explore when it engages with citizens is: Do citizens indeed have fewer (social) concerns about editing the epigenome than creating genetic modifications? Other questions include: What do citizens think about epigenetic reprogramming and how do they view possible applications in the future? The Rathenau Instituut will also facilitate the exchange of knowledge and opinions between citizens and scientists. This will allow researchers to incorporate values that citizens find important in the development of this new biotechnology. The Epi-Guide-Edit consortium will also invest in transferring knowledge through educational programmes.

Led by Pernette Verschure, professor of Functional Dynamics of the Epigenome (University of Amsterdam), researchers from various universities and institutes will develop a predictable methodology for editing the epigenome. To this end, they have received a €2.5 million grant from the Key Technology Programme from NWO.