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Disease and treatment

Enzyme discovery may revolutionize fertility treatment

A single enzyme appears to trigger the entire cell division process after sperm and egg fuse into a zygote. The discovery has long-term potential to revolutionize fertility treatment, says a researcher.

New Danish research shows that, at conception, when sperm and egg fuse, a single enzyme plays an unprecedented yet vital role in kick-starting the entire remarkable process that ultimately develops two microscopic cells into a living person.

This discovery may influence how the complexity of life is understood but may also improve the chances of success in artificial insemination.

“When we help people with fertility problems to have a child, problems often arise in the zygote’s initial cell divisions, in which it divides into two cells, and then four and then eight. Problems can arise in the mechanism that turns on the genes, and this enzyme plays a role in the process,” explains a researcher behind the study, Eva Hoffmann, Professor, Department of Cellular and Molecular Medicine, University of Copenhagen.

The research results have been published in Nature Cell Biology.

An enzyme unlocks the genetic machinery

At conception, when sperm and egg fuse, thousands of genes are turned on to help the two sex cells combine their DNA and then divide and turn into multiple cells.

However, these initial steps toward developing an embryo need to overcome some obstacles to get started.

The genes need to be turned on to encode all the proteins needed for the entire cell division process, and this is easier said than done.

As the sperm cell penetrates the egg, their genetic material is quiescent (inactive) and needs to be switched on as the embryo starts its life.

To ensure this, the egg has epigenetic marks or chemical modifications on its DNA, to help switch on the right genes, and this requires the newly discovered enzyme, lysine-specific demethylase 4A (KDM4A).

“Human cells have to go through two to three cell divisions before the tiny embryo even starts to run the processes automatically, and there may be some limitations to getting beyond these first cell divisions. KDM4A plays an important role in achieving a successful outcome,” says Eva Hoffmann.

Enzyme unlocks the cell’s genetic runway

Eva Hoffmann explains that the research results indicate that KDM4A opens up the sites of the genome needed for cell division and also keeps them open.

She compares this with keeping the runways at an airport open to enable the various aircraft to land.

KDM4A does not regulate the expression of the various genes but merely ensures access to all the other genetic processes.

“The process that the zygote goes through is really unique at this early stage of development. Everything has to be turned on at once, and up to 20,000 base pairs are made available for the genetic processes. Only then can the zygote divide and then begin to differentiate into different types of cells, but KDM4A is critical for initiating the whole process,” says Eva Hoffmann.

Probably the main reason when cell division goes wrong

Before the new study, researchers assumed that hundreds of things could go wrong in fertilizing an egg and that they all could cause the high percentage of unsuccessful fertility treatments, with 30–40% of all zygotes not developing beyond the first cell divisions.

But Eva Hoffmann and her colleagues speculated that the cause might not be several hundred factors but only one limiting factor.

To identify the limiting factor, the researchers examined how mouse zygotes express messenger RNA, which is the genetic link between genes and proteins.

They found that the genetic expression of the cell as a whole was not activated when the researchers turned off the gene for KDM4A.

“If the enzyme is not present to open the runways, the genome is inaccessible to outside molecules, which means that the relevant genetic programmes are not turned on at all,” says Eva Hoffmann.

Eva Hoffmann also explains that their research shows that KDM4A comes from the egg and not from the sperm. The runways are therefore also open in the eggs, and KDM4A keeps them open, but how KDM4A specifically unlocks the genome in the sperm cells is unknown.

“I think that everything happens in a programmed way. The processes are initiated in the egg, and then afterwards the genome in the sperm is programmed to get started as well,” she says.

Possible breakthrough in fertility treatment

Eva Hoffman explains that the study is relevant for both basic research and clinical applications.

The discovery of KDM4A suggests that exploring 800 genes may not be necessary in discovering why the first cell divisions sometimes fail after initial fertilization.

Solely examining the function of this one enzyme may be enough to determine why the process fails.

This insight naturally leads to possible clinical interventions that could increase the success of fertility treatments, and Eva Hoffmann thinks that injecting KDM4A into the egg during fertilization may be sufficient to unlock the genome and initiate cell division.

According to Eva Hoffmann, another future possibility is to inhibit the enzymes that KDM4A counteracts in the media in which the egg and the sperm are located to keep the runways open for the genetic machinery.

“Investigating this in human eggs and sperm is clearly a rational approach. However, we must get permission from the regional committee on health research ethics before we can begin these experiments. But if we can confirm what we found in mice and if we can influence the success rate of fertilization by catalysing the initial cell divisions, this will be a breakthrough in fertility treatment,” says Eva Hoffmann.

KDM4A regulates the maternal-to-zygotic transition by protecting broad H3K4me3 domains from H3K9me3 invasion in oocytes” has been published in Nature Cell Biology. In 2015, the Novo Nordisk Foundation awarded a grant to Eva Hoffmann for the project Mapping the Genomic Landscape in the Human Germline. Eva Hoffmann has recently been bestowed the lifetime honour of EMBO Membership in recognition of her remarkable achievements in the life sciences.

Eva Ran Hoffmann
Professor in Molecular Genetics, NNF Young Investigator
Chromosomes are rearranged and organized into new sets to create diversity as they are passed from parent to offspring through the germline. The genetic changes can be followed in populations, however this represents only a small proportion of the diversity that is generated in our germline. Men produce 500 billion sperm in their lifetime and women are born with two million eggs. Human reproduction is particularly error-prone. 50% of pre-implantation embryos have defects in their development and 20%-85% of human eggs have extra or missing chromosomes (aneuploidy). Maternal age is the strongest risk factor known for aneuploidy and our interests in reproductive aging also includes understanding the decreased quality as well as the decline in the number of eggs as women age. Our laboratory investigates the role of the DNA damage response and cell cycle proteins in governing the genetic changes that occur in the germline to generate diversity and maintain genome stability. In particular, we focus on those genes that when defective give to reproductive disease or cancer. We use a powerful combination of model organisms (mouse and yeast) as well as human eggs and embryos to explore this poorly understood area of human biology.