Focus Module – Epigenetics
Epigenetics has in recent times been highlighted as one of the potentially central mechanisms for an effect of early nutrition on developmental programming and long-term health. There is a wealth of research which now indicates there is a close interaction between our genes and our environment. In particular, findings show that the early environment plays a large part in shaping an individual’s phenotype. It is these early environmental cues that allow one genotype to display multiple phenotypes. This process is controlled by epigenetic mechanisms.
Epigenetic mechanisms are based on biochemical modifications of the DNA in a stable, heritable manner without changing the underlying DNA sequence. Major progress has been made and continues to be made in the field of epigenetics to date, and it remains a field at the forefront of scientific discovery. This might well give us new opportunities for insights into nutrition-related epigenetic changes that in the future could be translated into messages about the importance of a healthy lifestyle in producing healthy offspring.
In this module we introduce the topic of epigenetics and describe how epigenetic mechanisms are closely involved in human development and disease. This module further focuses on the environmental factors which effects fetal and infant development and what role these may play in altering the epigenome and thereby an individual’s predisposition to certain diseases.
This module has received accreditation by the German Medical Association with 15 CME credits.
Unit 1: Introduction to Epigenetic Mechanisms
DNA is the universal instruction book for how to build a living organism. In mammals, this equates to billions of individual letters from a four-letter alphabet (A- adenine; T-thymine; C-cytosine; G- guanine). In order to make a human this instruction book needs to be 'read', just as one might read a novel; with sentences, paragraphs and chapters defined and ordered accordingly.
All cells and tissues in a human body have the same genetic alphabet or code (DNA) but they can be vastly different in their size, morphology and function. What determines the difference between a kidney and a heart for example? How do cells maintain their identity after each cell division? The answer lies in the interaction between the genetic code, transcriptional regulators, and environmental cues, all of which combine to ensure that different parts of the instruction book of life are 'read' in the appropriate context and temporal order to ensure proper tissue development and function. This process is mediated by epigenetic modifications, which determine the accessibility of DNA to a variety of transcription and other regulatory factors, to determine the activity state of underlying DNA code. The epigenetic profile of individual cells acts as memory, allowing a cell to maintain its identity after each cell division. Therefore, epigenetic modifications can be thought of as punctuation marks in the instruction book of life, without which the genetic code would make little sense.
Unit 2: Epigenetics in Development
Epigenetic mechanisms play a very important role in human development. During pre-implantation development each lineage commitment is accompanied by a distinct change in gene expression pattern, mediated by a distinct 'shift' in epigenetic profile. Contrary to popular belief, gametes show a complex pattern of both histone and DNA methylation-mediated, non-genetic information, thought to play a key role in early post-fertilization development. Epigenetic change and cell differentiation is driven by small shifts in the microenvironment of individual cells. Mounting evidence suggests that epigenetic variation acquired in utero is a prime mediator for long-term programming effects.
Unit 3: Nutrition as a Key Regulator of Epigenetic Processes
One of the fundamental properties of epigenetic processes is their environmental sensitivity. This is critical from the very earliest stages of embryogenesis post fertilization as subtle environmental cues steer specific cell populations towards a defined identity - mediated in large part by the establishment of specific epigenetic profiles. The dynamic nature of the epigenome necessitates the constant availability of precursor molecules for specific processes (such as methyl donors needed for establishment of DNA methylation patters). Many such substrates cannot be synthesized by humans and must be sourced from dietary inputs. Not surprisingly therefore, diet is emerging as a key player in regulating epigenetic processes, not only by providing substrate molecules, but also by other influences. Some foods contain enzymes that directly regulate a range of epigenetic processes, or inhibitors of such enzymes, while general influences (over or undernutrition) can potentially 'program' the developing fetus in a manner associated with defined epigenetic variation. This is an emerging and exciting area of research, with nutrition-based interventions being considered as a potential mechanism to prevent (or even reverse) potentially harmful epigenetic variation established early in life.
Unit 4: Environmental Influence
Early life exposure to certain disadvantageous environmental influences can result in long-term changes to the epigenome. Stress, maternal smoking in pregnancy, infectious agents, heavy metals and assisted reproductive technology may all cause epigenetic changes in offspring potentially causing detrimental health effects. Prolonged and traumatic stress exposure in early life has been linked to various adverse health and psychological outcomes, including maladaptive stress responses (e.g. through impaired hypothalamic-pituitary-adrenal axis regulation) and cognitive and behavioral abnormalities. While evidence suggests a transgeneral effect for smoke exposure during the pre-conceptional period on the risk of several diseases, including cancer. DNA methylation have been reported in human cells following bacterial, viral or helminth infection. These changes may play a role in the development of immune-related disorders and many cancers previously associated with infectious agents.
Epigenetic changes caused by environmental influences are thought to play a significant role in the development and onset of many diseases. Continued research is needed in order for us to further understand the subtle intricacies of these effects.
Unit 5: Epigenetics and Disease
Gene: environment interactions are known to underpin much of disease risk in humans, including the level of penetrance (severity). Given the compelling evidence for a role of both genetics and environment on the epigenetic profile, and its key role in regulating all gene expression, it is not surprising that epigenetic variation is thought to mediate the effects of most gene:environment interactions and their role in disease. Disruption in epigenetic profile, primarily in early development, can occur at many levels.
Depending on the cause(s), detrimental epigenetic marks may be of varying severity and may manifest as adverse health outcomes from birth through to old age. Several severe human conditions result from gross epigenetic perturbation of gene expression early in development. More recently, it has become clear that one of the major features of all human cancers is disruption of the epigenome. Now, evidence is emerging that more subtle cumulative epigenetic change may play a key role in a range of non-communicable conditions (such as cardiovascular and metabolic problems) that represent the major burden of disease in developed and developing nations.