What is epigenetics?
Epigenetics is the software of a cell. It is a series of instructions that allows a given cell to properly use its hardware (the genetic code). Epigenetics is written in the language of biochemical tags, most prominently methylation of DNA. Methylation refers to the addition of methyl groups – biochemical tags – to DNA. These tags serve functions akin to bookmarks. They help the cell sift through the large amount of genetic material we inherit from our parents, and the bookmarks determine which gene should be active in a given cell to help it carry out its normal functions. This property is referred to as “epigenetics” to distinguish it from genetics, which refers to the study of the genetic code itself. Methyl groups are essential to the normal functioning of an adult cell.
Figure 1: The methyl group is a versatile biochemical tag that can be added to HNA, DNA or proteins and serves as a messenger. Methylation in DNA is akin to a bookmark that identifies areas that should be turned off or on.
Why study epigenetics?
Modern medicine has paid enormous attention to genetics and there has been remarkable progress in understanding diseases. However, many mysteries remain, not the least of which is that genetics fails to fully explain common ailments including cancer, diabetes and neuro-degeneration. It has become recently apparent that epigenetics can help fill the gap in knowledge. The concept is simple: disease can occur when the hardware is faulty (genetics) but also when the software is corrupted (epigenetics). The latter situation is only now receiving proper attention. We now know that redistribution of methyl groups onto DNA has been linked to diseases such as cancer. In essence, disruption of the biochemical tags (“epi-mutations”) can be as damaging as disruption of the genetic material itself (mutations).
Epigenetics and aging
Investigators at the Fels were among the first to point out that epigenetics are deregulated in aging cells and might influence lifespan. Lifespan varies considerably among mammals; the mechanisms of this old and fundamental observation in aging research remain somewhat mysterious. Understanding the process at the cellular and molecular level may lead to interventions that can prolong lifespan in general and thus prolong life in humans. Researchers have focused on changes in methylation of DNA with age and found that the methyl groups on DNA become progressively deregulated as we age (a phenomenon called “epigenetic drift”), and this deregulation is intensified in diseases associated with aging such as cancer. The rate of epigenetic drift closely mirrors the lifespan of different mammalian species. The faster the drift, the shorter the lifespan. In preliminary studies, Fels investigators found that calorie restriction in monkeys, in an experiment that showed prolongation of life by calorie restriction, resulted in significant slowing of epigenetic drift with age. Thus, the rate of epigenetic drift may be a determinant of lifespan across species, and could be an attractive target for the development of interventions aimed at prolonging life and reducing age-related diseases such as cancer, diabetes and neurodegeneration.
Figure 2: A model that unifies aging and cancer molecularly. In this model, epimutations that appear with age lead to cancer predisposition (and also predisposition to other diseases of aging). Reducing epimutations with diet or drugs may prevent cancer and prolong lifespan.
Epigenetics and cancer
Many decades ago, researchers found that the cancer “state” can be reversed by forcing cancer cells to undergo embryogenesis. This “reprogramming” proved that cancer has an epigenetic basis in addition to a genetic basis. Cancer is an example of a disease where both the hardware and the software are corrupted. Molecularly, this can easily be demonstrated by studying methylation in cancer cells compared to normal cells. Importantly, while hardware cannot be easily changed in humans, the software can be rewritten by drugs that change the biochemical tags in question. Indeed, several of these drugs are in use in cancer therapy, thanks in part to efforts of investigators at the Fels. Current projects include using methyl groups to predict cancer risk, response to chemotherapy and long term outcome, as well as to develop targeted drugs that reprogram the cancer software, an approach that has been dubbed “diplomacy in the war on cancer”.
Epigenetics, nutrition and the environment
The biochemical tags that constitute the epigenetic code are constantly renewed and are therefore subject to errors. These errors (epimutations) underlie some of the diseases of aging such as cancer. Importantly, these errors can be compounded by diet and environmental exposures. Nature has shown us that the environment can modulate epigenetics, and this has received too little attention from regulators and Public Health experts. Investigators at the Fels have shown that some dietary components can alter epigenetics when given over long periods of time, and thus could have unexpected effects on disease. They have also shown that manipulation of stem cells, for example by in-vitro fertilization, can result in important differences in the biochemical tags that constitute epigenetics. Fels investigators are also studying whether viruses and common exposures to chemicals (in plastic, for example) can change the epigenetic software and lead to disease by unrecognized ways.
Queen Bee vs. Worker Bees
Queen Bee Larvae in Royal Jelly
Figure 3: A natural example of epigenetics, nutrition and the environment. Queen-bees and worker bees have the same genetics (hardware) yet are very different physiologically. For example, queen bees live much longer than worker bees. These differences can be explained by epigenetic differences that has been traced to nutrition – unlike worker bees, queen bees are bathed in royal jelly as larvae, and only eat royal jelly as adults. Royal jelly contains molecules that modify epigenetics.
The epigenetics program at the Fels Institute
There are currently more than 10 faculty members at the Fels institute with interest in epigenetics, constituting one of the highest concentrations of expertise in the area. Overall, there are more than 25 researchers at the bench studying various aspects of epigenetics, from pre-natal and infant nutrition all the way to drug development. The program aims to increase understanding of the process, develop markers and tools to measure it, and develop drugs that can modulate it safely. Overall, our goals are to understand aging and diseases and prolong life through nontoxic interventions that target epigenetics.