Transgenerational Epigenetics

Updated: Aug 22, 2018

By Zach Finzi


Genetics is the field of study which focuses on patterns of inheritance and heritability in genes from parents to offspring. This is often considered the field of study which focuses on the biological components that give rise to the development of an individual. Notably, over the course of an individual’s lifetime, biology is not the only factor that contributes to the phenotypic expression of an individual. Significant research has focused on how environment plays into not only the psychological and behavioral profile of an individual, but also the genetic identity of their cellular environments. Now, current research is attempting to elucidate if environmental changes to gene expression in cells can be passed on from generation to generation. Understanding this concept could reveal a whole set of unexplored territory in the field of genetics, and the importance of a parent’s environment on the genetic persona of their offspring.


The most prominent form of environmental alteration on genetic expression is induced through epigenetic modification of DNA. Epigenetics refers to changes in DNA structure, which allow for genes to be turned “on” or “off”, or expressed in a different and more specific way. Cells can therefore be exposed to environments which cause for epigenetic changes to their DNA, which in turn would shift their genetic profile (i.e. the genes that they express and proteins that they make). When we experience something in our external world, whether through mental or physical exposure, these effects can reach us on a cellular level. One example of this can be our dietary habits, which expose our cells to various macromolecules which may induce epigenetic alterations. DNA methylation is the process through which a methyl group is added to an area of a DNA molecule, essentially turning a gene “off.” Another form of epigenetic change occurs through histone modification. Histones are proteins which form octamers (composed of 8 units) that work to condense DNA by wrapping their long helical structure around DNA’s helical shape. This coiled region of DNA is referred to as a nucleosome. This allows for some of the DNA to be exposed (“on”) and others to be hidden (“off”). Modification of histone molecules allows for the movement of the DNA from an exposed to a hidden position, or vice versa (Rissman et al. 2014).

Rissman et al. 2014

As we go through life, constantly changing our external exposure and shifting our genetic profiles in response, epigenetic modification of DNA turns genes “on” and “off” in response. During constant exposure to a given environment, such as a consistent unhealthy diet, epigenetic change can become stagnant. Some current studies, have even suggested that these stagnant epigenetic changes to DNA structure and gene expression can be passed on from generation to generation. Typically, during development of the mammalian embryo, epigenetic alterations in sperm and egg cells are almost entirely wiped out during a reset process of epigenetic changes (Rissman et al. 2014). This makes it seem that no environmental effects of epigenetics could possibly be transmitted from one generation to the next. However it is noted that 1% of nucleosome structures are maintained in mouse sperm (Wei et al. 2013), and roughly 15% are maintained in human sperm (Erkek et al. 2013). It is within this thin margin of transmitted information that Wei et al. found a remarkable phenomenon in transgenerational inheritance of paternal mice environments.


Rissman et al. 2014

Wei et al. tested this notion by exposing paternal mice to a high-fat diet and impairing their fasting glucose to see the effect on their offspring. The goal of this experiment was to see if mice exposed to a prediabetic environment would undergo epigenetic changes in response, and pass these alterations on to the following generation. Paternal mice exposed to the prediabetic environment were found to have higher body mass, fat content, food consumption, plasma glucose levels, and several other elevated biomarkers indicative of a high fat diet. When examining the offspring of prediabetic male mice to those of non-prediabetic mice, there were clear indications of reduced insulin sensitivity and higher levels of blood sugar. Patients with diabetes have difficult with high glucose levels and reduced efficacy of insulin. These results clearly show that the phenotypic expression of prediabetic male mice offspring exhibited diabetic qualities, even when raised on a normal diet (Wei et al. 2013).


In addition to the heightened diabetic biomarkers in these offspring, genetic observations showed several differences in protein quantities that could explain these alterations. Proteins typically associated with glucose transportation, glucose dependent insulin release, and insulin deactivation were found in altered levels within prediabetic male mouse offspring. Researchers also found higher levels of methylation on two regions of DNA in prediabetic male mouse offspring related to genetic expression in pancreatic cells. Pancreatic cells regulate insulin release and blood glucose responses in the body. What this data shows us is that changing diet in male mice may result in transgenerational inheritance of epigenetic changes to DNA methylation. While most epigenetic changes are wiped out during embryo development, some changes can be passed on, as shown with this study by Wei et. al. Further, high-fat diets in male mice, increase the risk of diabetic phenotypes in their offspring (Wei et al. 2013). If we see this level of detrimental inheritance in unhealthy mice, found only in 1%, what does a 15% inheritance in epigenetic material mean for humans?


In a study conducted by Kaati et. al. in 2002 concerning three generations of families from Sweden, a similar finding was made. The researchers examined the diets of adolescents during their slow growth period (SGP) in the late 18th century through historical records of food access (measured by regional farming success) and proximal location to food sources. The same form of analysis was conducted on their lineage for the following two generations. The researchers finally examined the rate of cardiovascular related death, specifically pertaining to diabetic mortality, in comparison to transgenerational diet. What was shown was that paternal grandfathers who had been exposed to a surplus of food during their SGP yielded grandchildren who were four times as likely to die from diabetes mellitus. No genetic data has been analyzed for this finding, and therefore the direct linkage to epigenetic inheritance cannot be drawn. However, it is clear that dietary environment has transgenerational implications for both mice and humans.


It has long been known that genes and environment, nature and nurture, are a key role in the development of each and every individual. Our species is highly adaptive to our environment and contains a wide diversity of genetic material which can shift in and out of activity in response. What this research now elucidates for the field of genetics and the broader public, is that environments can be multi-generational. You may not share the same actions or setting that your parents grew up in, but traces of their lifestyle can still be found on your epigenetic track record. While it is still uncertain how epigenetic inheritance works within humans, and the extent of the effect, we should not take the concept so lightly. The implications of our behavior and what we expose ourselves to, may be more important than they appear to be.


References:


Erkek S, Hisano M, Liang CY, et al. (2013). Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa. Nat Struct Mol Biol, 20, 868–875.


Kaati G, Bygren LO, Edvinsson S. (2002) Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. European Journal of Human Genetics, 10, 682-688.


Rissman E, Adili M. (2014). Transgenerational Epigenetic Inheritance: Focus on Endocrine Disrupting Compounds. Endocrinology, 155(8), 2770-2780.


Wei Y, Yang C, Wei Y, Zhao Z, Hou Y, Schatten H, Sun Q. (2013) Paternally Induced Transgenerational inheritance of susceptibility to diabetes in mammals. PNAS, 111(5), 1873-1878.


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