The success of infertility treatment depends on the early stages of embryo development

To better understand the effectiveness of infertility treatment, it is necessary to study the processes that occur during the first week of embryonic development. At this stage, the embryo begins to follow guidelines encoded within its own genome rather than primarily relying on gene products received from the mother.

According to data from the National Institute for Health Development, nearly 6 percent of all children born in Estonia in 2023 were conceived through fertility treatment. On average however, only one out of three treatment cycles results in pregnancy. A significant proportion of these failures are due to embryos that do not progress beyond the earliest stages of development.

In his doctoral thesis, defended at the Institute of Molecular and Cell Biology at the University of Tartu and the Karolinska Institute, Barış Yaşar investigated the root cause of this problem by focusing on the mechanisms of embryonic genome activation (EGA). EGA is a process during which the embryo progressively reduces its reliance on gene products derived from the mother’s egg cell and instead activates its own genetic program.

In humans, EGA occurs during the 4-to-8-cell stage, approximately two or three days after fertilization. This marks a crucial turning point in embryonic development: much like a newborn becoming independent after the umbilical cord is cut, the embryo starts directing its own development through activation of its genome. If the timing of this transition is disrupted, embryonic development may stall.

Human and cattle embryos are similar

Research into the early developmental stages of the human embryo is complex and strictly regulated from an ethical standpoint. Therefore, Yaşar used bovine embryos as a model system. Bovine gestation is similar in length to human gestation, both mammals typically give birth to a single offspring, and their egg cells are also similar in size.

In the first part of his thesis, Yaşar mapped the bovine counterparts of human PRD-like homeobox genes. These genes encode transcription factors—proteins capable of activating other genes. In humans, many of these genes are activated during the pre-implantation period, before the embryo attaches to the uterine wall.

Together with colleagues, Yaşar demonstrated that humans and cattle express similar genes during early development. In addition, he identified potential start sites of active genes in bovine oocytes and early embryos. This made it possible to identify potential regulatory factors that may contribute to the activation of the embryonic genome in bovine embryos.

Preparation is necessary

These activators turned out to include several PRD-like transcription factors and other regulatory proteins. This highlights that embryonic development depends on the precisely timed cooperation of numerous genes. Genetics alone is not enough; in addition to genetics, various environmental factors such as oxygen levels can influence embryonic growth.

Yaşar specifically focused on a genomic region in bovine that contains the gene DUXC, whose human homologue is DUX4. He showed that the genomic organization of these genes is highly similar between two species. It turned out that the expression of both genes follows a highly similar and tightly timed pattern during early embryonic development. Disruptions to this pattern can halt the embryo’s subsequent development.

Although the doctoral thesis does not yet provide fertility clinics with ready-made treatment guidelines, it helps researchers better understand why fertility treatments often fail. If we better understand how and when an embryo’s genome is activated, we can make artificial insemination procedures significantly more effective in the future. The cattle industry is also eagerly looking for this knowledge, as the income earned by cattle farmers depends directly on the success of embryo transfer.

The doctoral thesis is based on three peer-reviewed scientific articles published in leading international journals, including BMC Genomics and a preprint, in which Barış Yaşar is the first author.

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