September 28, 2017

What if you could improve the safety and success of assisted reproductive technologies (ARTs) like in vitro fertilization? ART births continue to rise, even as the U.S. birth rate continues to decline, yet progress is still needed. Safer methods of fertility treatment are just one of the goals of Magee-Womens Research Institute’s Mellissa RW Mann, PhD research through the study of epigenetics.

Mellissa Mann, PhD

Epigenetics simply means “on top of genetic material or the genes.” It is not about the DNA itself, but rather the markings on top of those genes that control which genes are to be expressed and which are not. These chemical modifications to DNA could influence everything from hair growth to more serious genetic changes that could result in cancer or other diseases.

Dr. Mann and her team are focusing on embryos in the first week of development, which may be one of the windows of sensitivity for potential epigenetic errors. But an embryo at this stage has roughly one to one hundred cells. How is it possible to study such little material?

Dr. Mann’s lab at Magee-Womens Research Institute has had the incredible opportunity to develop new tools and technologies to ask the questions that need answered. “For my lab,” Dr. Mann explains, “it really is a unique research niche to be able to address the questions in these very early embryos. We’re probably one of less than a handful of labs in the world that studies epigenetics in these very early stages of development.”

When it comes to fertility, children conceived by ARTs have an increased risk for premature birth and low birth weight, and possibly genomic imprinting disorders, a particular type of genetic disorder. These adverse outcomes may be due to epigenetic errors caused by instability in these imprinted marks. By using the mouse as a model system, Dr. Mann is investigating the effects of hormone stimulation or in vitro culture on the early stages of life, a critical time in the development of these epigenetic markers.

Epigenetic Errors: What Effect Do They Have?

Many embryos don’t develop any sort of epigenetic error and then there are some that do. Dr. Mann’s lab is looking at one single embryo at a time to better understand why these errors occur. “What we’ve found is that some embryos might have an epigenetic error at one of the master control switches, and some of the embryos may have multiple errors.”

By looking at these errors in early stages of embryonic development, namely preimplantation, Dr. Mann and her team discovered that, later in development, many of the errors were found in the placenta, and fewer errors were present in the embryo proper. “We think this may relate to what is seen in humans where there’s been an association with assisted reproduction and the development of some imprinting disorders.” While these are relatively rare in the human population, “there could be potential effects where, if these errors are occurring in the placental tissues, there may be more errors in implanting or in proper growth of the placenta, and in turn the fetus.”

Dr. Mann’s team is paving the way for discoveries that might improve the procedures used in assisted reproductive technologies and make advances in fertility treatments. “The ultimate goal is to make these procedures as safe as possible for couples undergoing fertility treatments, because this is one of the big advances in modern medicine—to allow people who are having difficulty with fertility to possibly have their own children.”

Epigenetics’ Inner Workings

In order to better understand the relationship between assisted reproductive technologies and epigenetics, we have to take a more detailed look at the science behind it.

Epigenetics refers to chemical modifications to the DNA that tell the genes when to be turned on and off. “For example, as muscle cells are developing, they don’t need the genes that are involved in the brain, heart, fat, or any of other tissue, so these genes will be turned off and the genes involved in developing the muscle will be turned on,” Dr. Mann explains. Yet epigenetics has a wider effect.

The phenomenon of genomic imprinting relies on these epigenetic mechanisms. Genomic imprinting originally came from the idea of animal imprinting, when a baby will bond to the mother. When this concept is translated to human biology, Dr. Mann explains, it “is more of a molecular imprinting where genes that come from the mom acquire an epigenetic mark that tags it, saying ‘This gene was from mom.’ Different genes from the father will be tagged with ‘This gene was from father.’ Such that, when the sperm and the oocyte produce an embryo, in that embryo you will have a gene that will be tagged with a mark that says it was off when it was from the mother and on when it was from the father, or visa versa.”

These imprinted genes are often located in clusters—typically consisting of 3-20 genes; in that cluster is a master control switch region called the imprinting control region. This master control switch stores the epigenetic information and coordinates which genes—maternal or paternal alleles—will be turned off. “We don’t yet know what designates [a gene being marked as] “off” or “on”, but we know it’s specific to the differences in the development of oocytes and how they treat the DNA versus how sperm treats the DNA.”

When epigenetic information is disrupted, it can cause errors in the imprinting control region that alters expression of the genes in the cluster, leading to certain genetic diseases such as Beckwith-Wiedemann and Angelman Syndrome, or even cancer.

Assisted Reproductive Technologies’ Window of Susceptibility

It is during two critical developmental periods in the assisted reproduction process that epigenetic information has the potential to be disrupted: oocyte development and preimplantation development.

During oocyte development, a large number of these master switches are acquiring an epigenetic mark called DNA methylation, which is typically associated with the gene being off. This time period for acquiring DNA methylation marks at the exact same time that oocytes become responsive to treatment from hormones that are being injected into mom. Hormone treatments may disrupt this epigenetic information, leading to errors in these markers.

After the embryo is formed during fertilization, these epigenetic marks are protected during the time of preimplantation development. Dr. Mann takes particular interest in this phenomenon as, “What’s interesting is that the rest of the genetic material from the sperm and oocyte is being wiped of its epigenetic information with the thought that cells within an embryo need a blank slate in order to develop all the cell types in the body as the embryos grows.”

Any disruption in these processes has the potential to lead to imprinting errors. However, by looking more closely at embryos during this time, researchers can investigate which procedures may possibly lead to these imprinting errors and how the protection of epigenetic information occurs. Dr. Mann’s research will help to shed light on what aspects of ARTs cause these errors and how to better protect epigenetic information for safer fertility treatments in the future.

There may even be broader implications of Dr. Mann’s research yet to come. Researchers still don’t quite have an understanding of what environmental exposures may lead to epigenetic defects, as epigenetics are susceptible to change as a result of environmental factors, such as nutrition or environmental pollutants. Dr. Mann’s research may have a hand in helping to identify windows of susceptibility for epigenetic errors due to these external factors.

Further effects of epigenetic research are sure to leave a lasting impact on families for years to come. Dr. Mann is hopeful. “I think we’ve got a great opportunity to make some headway in the discovery of how these epigenetic mechanisms are regulating early development and genomic imprinting.”

Learn more about Dr. Mann’s and MWRI’s ongoing research into the relationship between epigenetics and advances in fertility treatments.