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If you have not heard yet about “epigenetics,” you will probably be surprised, as its evolution also surprised many of the scientists who discovered this new layer of genetic activity that determines who we are and, often, what diseases we will or will not develop. The term “epigenetics” has been in the medical literature for approximately a century and denotes the study of changes in all organisms caused by modification of gene expression (i.e., what the gene does) but not by changes in the gene itself (i.e., for example, it does not involve the use of CRISPR-Cas9 to switch out a specific mutation in a gene).
Though some work has been done for a long time, it has come into focus only after the year 2000, when a number of groundbreaking studies were published. Considering epigenetics clinically relevant can be traced to the so-called “fetal-origin-hypothesis,” associated with David J. Barker, a British epidemiologist who made the claim in 1990 that major medical conditions in adult life could have been caused by environmental factors those individuals had been exposed to in utero. His specific claim was that intrauterine growth retardation (IUGR), low birth weight and premature birth were causing hypertension, coronary heart disease and non-insulin-dependent diabetes later in life (the so-called Barker Theory/Hypothesis).
Mechanisms of epigenetics. Epigenetic changes include DNA methylation and histone modification, both of which have implications on what diseases we do or do not develop throughout life. Public domain image from National Institutes of Health.
Studies of offspring who lived in their mothers’ uteri during famines confirmed the importance of quality of intrauterine life on future health. For example, during the German occupation, the winter of 1944-1945, widely known in The Netherlands as the “Hunger Winter,” was extensively investigated and found to show effects on fat deposits in women, but not men, by age 59. There was also a modest association with blood pressure and some other physical parameters. Most importantly, people who were in utero during the famine died after age 68 at an accelerated rate by 10%.
Results from this and other famine studies greatly enhanced the concept of “epigenetics,” because by trying to understand how a famine while in utero could affect a person’s life-long health, researchers found out that genes of fetuses in utero were strongly affected in their functions later in life by the environment a woman’s uterus offered during gestation. Investigators, indeed, recognized that the nine months in utero were the most important period in a human’s life in determining how much or how little genetic activity genes will produce during a person's life. Though environmental factors can also influence gene activities after birth and throughout life, the most fundamental impact on gene function from “epigenetics” occurs in utero.
This observation has particular relevance for women going through egg donation, because they frequently ask whether “they contribute anything” to the baby’s genetic make-up in egg donation cycles. And the answer, of course, is that, while they do not contribute maternal genes to the baby, they determine, in very significant ways, how these genes will work during the individual’s lifetime. And, maybe even more importantly, how genes are “programmed” during the in-utero period can also be inherited into future generations. Therefore, your grandparents can also be responsible for how your genes are functioning today and you may be important not only for how your own child’s genes function but also how your grandchild’s genes will be functioning, even if you used donor eggs.
Faults in the processes for copying of DNA during every cell division can cause epigenetic changes that can be inherited for up to five generations. Those changes then result in loss of molecular processes that, normally, are responsible for silencing genes. If these mechanisms are lost, no more silencing takes place and, often, disease-causing functions of genes are activated. Loss of inhibition is, therefore, often undesirable.
“Epigenetics” uses chemical/biological signals that regulate how much functional activity a gene will be putting out. It is almost like setting a thermostat on an AC unit for how much air it blows at any given time into a room. Using the same analogy, instructions can be time-limited or be set for a lifetime. Most importantly, without making any changes to the DNA structure itself, the gene can even be completely shut off like a thermostat, stopping all of its protein production and/or interaction with other genes.
Such chemical reactions can come in a variety of different formats, all now quite well understood. The most studied is the so-called methylation, a process in which methyl groups are added/removed from DNA, also increasingly recognized to reflect age and longevity. Some direct-to-consumer genetic testing companies, indeed, have started offering reports on methylation status as a rather flimsy representation of “genetic age.” When located in a gene promoter, DNA methylation typically suppresses gene transcription as noted above, while demethylation enhances gene transcription. Another chemical process involved in “epigenetics” is histone modification, a post-translational modification of messages. For example, acetylation of histones increases expression of genes via activation of transcription. Deacetylation does the opposite.
“Epigenetics” basically means that our environment constantly affects how our genes are working. It does not stop with the time we are spending in our mothers’ uteri. While those nine months exert probably the biggest influence of any time period, the environment in which we grow up and live in steadily modifies the output of our genes. What we eat and drink, whether we smoke, use drugs, are on medications, where we live, what chemicals we are exposed to, how much we sleep and/or exercise, all matters. And then there is the aging process itself, that changes our epigenetics.
Because we all live such different lives, “epigenetics” is also what makes us so different from each other. This recognition has revolutionized medicine in recent years as it has led to the evolution of personalized medicine, also called precision medicine in all medical specialties. In infertility, CHR has, of course, been on the forefront of these developments by offering now for a good number of years increasingly individualized medical care to our patients. Steady readers of these pages will be fully aware of this fact because we have repeatedly pointed out in the VOICE how radically individualization of fertility treatments over the last decade has changed the treatments we are offering to our patients.
Finally, it is also important to point out that because “epigenetics” are constantly affected by environmental impacts, they, of course, offer opportunities for reversal of detrimental programming. While we are not yet at a point where we in very specific and directed ways can turn on and off selected groups of genes via environmental modifications in order to affect certain health care goals, we are certain that this day will come. In the meantime, it, however, behooves us all to recognize that how we live our lives does matter and does affect our genetic strengths and weaknesses.
This is a part of the April 2019 CHR VOICE.
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.
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