Embryonic gene activation (EGA) is the process by which an embyo begins to transcribe its newly formed genome. A fertilized embryo is initially transcriptionally quiescent as it is trapped in a transcriptionally oppressive environment. Maternal mRNA and proteins deposited in the mature oocyte during oogenesis, drive the first cell cycles. EGA is essential in order to synthesise new proteins and further cleavage to take place. The time taken for embryos to break out of this environment and commence EGA varies between species: 4-cell stage in humans, 2-cell stage in mice (Figure 1).
Many maternal transcripts code for transcription factors that allow the transcription of essential embryonic proteins required for EGA to take place e.g. translation initiator proteins eIF 1A. However, these maternal transcription factors require post-translational modification such as phosphorylation, to allow them to function.
A small number of embryonic genes are active before the 4-cell stage. These genes code for proteins involved in stabilising and controlling the activity of maternal mRNA and proteins. Embryonic proteins increase the stability and translational ability of mRNA by polyadenylating the 3' end of mRNA untranslated region (3'UTR). Ca2+ released at fertilisation is linked with the translation of maternal mRNAs as inhibiting Ca2+ release prevents mRNA translation. It is thought that maternal mRNAs are sequestered by translation inhibiting complexes. Release of Ca2+ causes phosphorylation of this inhibiting complex, releasing the mRNA and enabling polyadenylation and translation to take place. Deadenylation of maternal mRNA 3'UTR by embryonic proteins destabilises the mRNA and targets it for destruction. Maternal proteins are regulated at the post-translational level by modifying the proteins phosphorylation state. Alternative phosphorylation states of proteins mediated by embryonic kinases and phosphatases can stimulate protein activity, target the protein for degradation or change the proteins subcellular location. Modification and degradation of specific maternal mRNAs and proteins is important for regulating embryo development before main EGA.
In order for EGA to take place, the embryo must be released from its transcriptionally oppressive environment and synthesise its own transcriptional and translational machinery. The limitted size of sperm means that paternal DNA must be hypercondensed in order to fit into the nucleus. This is achieved using small proteins, known as protamines, which are associated with the paternal DNA in a nucleoprotein complex. The hypercondensation of the embryo's paternal chromosomes renders them completely inaccessible to transcription. Maternal proteins therefore replace the protamine packaging with histones; proteins normally associated with nucleic acids, which allow the formation of organised chromatin. Histones H3 and H4 replace the protamines and make the chromosomes accessible to transcription.
At the 4-cell stage, the embryo's chromatin has been remodelled to allow transcription to take place and the embryo's own transcription and translation machinery has been synthesised. The embryonic genome is now fully active and takes over transcription and translation of its own metabolic, cell cycle and apoptosis regulating proteins. Maternal proteins and mRNAs are degraded progressively early on in the 4-cell stage (Figure 1).
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