Sperm fertilizing the eggs is the beginning of a new life. Maternal and paternal genetic information, which storing the organism's body structure, binds together after fertilization.
However, at this early stage of life, DNA remains in an inactive state in the nucleus. Although the first division of the zygote cell occurs with the help of maternal factors stored in the egg, the synthesis of new embryonic products is necessary for further development of the embryo, which requires exposure to the embryonic DNA. In a new study, Kikue Tachibana and her team of the Max Planck Biochemistry Institute, Germany, confirmed that the universal pioneer factor Nr5a2 activated embryonic DNA. The results were published online on 24 November 2022 in the Science journal Science, with the paper title "Zygotic genome activation by the totipotency pioneer factor Nr5a2".
The beginning of life is a fascinating process in biology. Female eggs are fertilized by their fusion with male sperm cells. From the first cell of this embryo, the whole organism can develop. What molecular processes occur on the DNA of a fertilized egg that make it possible for the fertilized egg cell to produce a new organism? Together, the Tachibana team studied this issue using a mouse model.
It is known that so-called pioneer factors tend to bind to specific regions of inactive DNA to activate them. Finding out what these pioneer factors are in zygote cells is the subject of this new study.
Tachibana said, " The core team of this new study consists of experts in embryology, biochemistry, bioinformatics, microscopy, and genomics. Together, we were able to discover clues in the genome, discover the transcription factor Nr5a2, and investigate its mechanism of action inside and outside the cell.”
Totipotency pioneer factor Nr5a2
The Pioneer factor has the ability to bind to a tightly compressed DNA. They belong to a large family of transcription factors. They bind to specific sequence patterns on the DNA to transcribe the gene sequences.
Imre Gaspar, co-first author of the paper and an expert at the Max Planck Institute of Biochemistry, explained, " We found common sequence patterns for the early mRNA molecules produced in the embryo and were able to find several sequence motifs. The sequence motifs we found are close to each other, forming a so-called supermotif (supermotif). This newly discovered supermotif resembles the known sequence motif SINE B1 element and has a very close relationship to the highly conserved ALU elements in the human genome. These elements are also known as 'jump genes' because they can move from one location in the genome to another at certain cellular stages (such as the early embryo).”
Nr5a2 binds to this supermotif. Johanna Gassler, co-first author of the paper and an embryologist at the Max Planck Biochemical Research Institute, said, " Initially, Nr5a2 was found in the liver. In the field of developmental biology, Nr5a2 is known to be important in the later stages of embryo implantation. Just how important Nr5a2 is after fertilization is unknown. In our experiments, we were able to find that once Nr5a2 is blocked, most early embryonic mRNA molecules are no longer produced. Furthermore, the further development of the embryo was also inhibited. This suggests that Nr5a2 plays a central role in the earliest stages of embryonic development.”
Using the most recent biochemical and genomic approaches, these authors tested how Nr5a2 functions in early development. Wataru Kobayashi, co-first author of the paper and biochemist at the Max Planck Institute for Biochemistry, explained, " We experimentally confirmed that Nr5a2 can open up inactive DNA regions, making more DNA regions available for subsequent transcription processes."Thus, the zygote genome is activated at a two-cell stage, and the embryo eventually develops into a fully dynamic organism.
Tachibana said, " Finding Nr5a2 as a key factor driving genome activation is an important step towards achieving a mechanistic understanding of the onset of life. It is also clear that there must be other facilitators to be identified. So far, our study provides a conceptual framework that can explain how transcriptional activation occurs robustly in early embryos to ensure embryonic development as an intact organism.
