"The answers to these questions could partly be found in the epigenome", says Holger Wagner-Thelen, PhD student from TA 4. As part of his dissertation, he investigates potential relationships between diet and epigenetic mechanisms involved in progression to the dementia stage of the Alzheimer's disease. "Epigenetic mechanisms have an impact on gene expression. These mechanisms can either increase or reduce gene expression. However this process does not alter the DNA itself, but rather affects frequency and strength with which DNA is read", explains the scientist. Epigenetics should be distinguished from genetic changes because the latter produces modifications in the DNA sequence due to mutations. Importantly, genetics and epigenetics dependent on each other because the DNA sequence (genetics) itself can also influence epigenetics. Furthermore, environmental factors may exert their effect on disease risk through epigenetic changes. In fact, "from a translational perspective, epigenetics has more direct application as epigenetic changes are potentially reversible through changes in environmental factors. This means that if certain epigenetic changes have occurred, they will not necessarily be passed on to the next generation and can also be reversed." Wagner-Thelen explains this context with an example: "Researchers were able to show in mice that the diet of a female animal had an influence on the expression of the fur colour gene in the offspring. If these offspring was fed differently from the parents, the expression of the gene was redirected and changed again in the following generation." Another prominent example for the strong influence diet can have on gene expression is the queen bee. "The major difference between a queen larva and a bee larva is the food. The single fact that the larva, which is to become the queen, is fed with royal jelly, causes about 500 genes to be expressed differently from the other bee larvae. This differential gene expression program leads the queen bee to look different and to live longer." explains Wagner-Thelen.
These changes in gene expression are based on different mechanisms - the most commonly investigated is the methylation of DNA. "By methylation, certain areas of DNA are chemically altered by addition of a methyl group. The basic unit within these areas is formed by two base pairs, i.e. CpG (Cytosine-Phosphatidyl-Guanin). In the CpG dinucleotide, the base Cytosine and Guanine are linked together via a phosphate group, and they are relatively rarely found in the genome. An interesting observation is that often clusters of CpG-dinucleotides are found shortly before the coding sequence of a gene starts. These clusters are called CpG-Islands, and are supposed to have regulatory function in gene expression. If a methyl group is attached to the Cytosines within these CpG-Islands, the transcription factors cannot bind and the following gene segment can no longer be read - the gene is then switched off."
For his dissertation, Wagner-Thelen measures exactly these methylations in the genome and correlates them with biomarkers for nutrition. "For DietBB, a group of participants of the AgeCoDe study who developed Alzheimer's dementia was examined and compared to methylation patterns and biomarkers of matched healthy controls, also extracted from AgeCoDe. The AgeCoDe study is a prospective cohort study, whose participants are not demented at the beginning of the study and are at least 75 years of age or older. The AgeCoDe study has been running since 2003 and detailed clinical information and blood samples are collected from the participants at different follow-ups. These blood samples can be used to measure the methylation of DNA and specific biomarkers, which reflect the diet of the participants to a certain extent. We associated these biomarkers with the methylation of specific genomic regions and thus we are able to correlate the influence of the diet on epigenetic changes of the DNA. In a further step, it will be interesting to see whether these epigenetic mechanisms could also be involved in the development of Alzheimer's disease. In the context of DietBB we are also working on the interaction between genetics and epigenetics and their contribution to complex diseases such as Alzheimer's disease", says Wagner-Thelen.
"Twin studies showed that lifestyle can have a strong impact on epigenetics. Observations on monozygotic twins showed that twins in their younger age are epigenetically closer to each other than later in life. Another observation suggested that the influence of lifestyle on the epigenetics can also be relevant for the development of Alzheimer's disease: one study described a pair of monozygotic twins where one of the twins developed Alzheimer's disease and the other, genetically identical twin, showed no signs of Alzheimer's disease until his death, which was 19 years after his brother's first symptoms. This suggests that epigenetics can play a central role in the development of complex diseases."
Epigenetics provides many indications how our lifestyle can influence our gene expression. Wagner-Thelen's conclusion is: "It will take some time until we understand exactly what contribution epigenetics makes. In this context, for example, it has not yet been clarified whether epigenetic changes are the "maker" or a "marker" of a disease."
Text: Maike Gutmann, DGE (TA6)