Evolution of zygotic genome activation across metazoans

Evolution of zygotic genome activation across metazoansEvolution of zygotic genome activation across metazoans

Current lab members: Israel Campo-Bes, Luis P. Iñiguez.
Former lab members: Bárbara Pernaute, Chris Wyatt.
Funding: Plan Estatal MICINN, Marie Skłodowska-Curie Actions, Boehringer Ingelheim, La Caixa Foundation, CRG.

One of the few universal developmental processes across animals is the maternal-to-zygotic transition, in which embryogenesis goes from being orchestrated by the maternal transcripts and proteins deposited in the oocyte during oogenesis to being controlled by active transcription of the zygotic genome. In every species, this transition involves the same basic steps: (i) the maternal contribution is partly cleared (passively and actively), and (ii) the zygotic genome is activated, usually through a first minor wave with transcription of a few key genes and then a second major wave, in which hundreds or thousands of genes are switched on.

Zygotic genome activation (ZGA) is thus a fundamental step for subsequent cell differentiation and organogenesis. However, the stage when the ZGA occurs and the associated transcriptomic changes are unknown for the vast majority of animal lineages, as they have only been studied in a handful of model organisms. In these research line, we are investigating ZGA across dozens of animal species from more than 10 phyla and spanning 700 million years of evolution. We will address how the transcriptomes change at the gene expression level during this process, and elucidate the underlying developmental and genomics causes for ZGA variation. Moreover, we will specifically probe how transposable elements are regulated in each of these species to try to identify oddities and commonalities.

In addition, we will ask how alternative splicing changes during ZGA. We recently found that mammalian blastomeres undergoing ZGA exhibit the highest levels of exon skipping of all cell and tissue types (Wyatt et al, Science Adv 2022). This striking transcriptomic diversity is temporary, lasting only 1-2 cell cycles, and is due to a developmentally programmed splicing failure: as during oogenesis some core spliceosomal components are not deposited at sufficient levels, splicing partially fails when zygotic transcription starts. Genes harboring these skipped exons are enriched for DNA damage response functions, in line with the low reparative response of early embryos. Remarkably, by partially rescuing this programmed splicing failure we increased DNA damage response in mouse 2-cell embryos. Therefore, we will now ask whether similar mechanisms and functional consequences exist in other animal groups.

In summary, the results expected from this project will provide unprecedented information about the tempos, modes and evolution of the key early developmental processes of maternal-to-zygotic transition and ZGA across metazoans.

Related publications:

  • Wyatt C.D.R.*, Pernaute, B.*†, Gohr, A., Miret-Cuesta, M., Goyeneche, L., Rovira, Q., Bogdanovic, O., Bonnal, S., Irimia, M.† (2022). A developmentally programmed splicing failure attenuates the DNA damage response during mammalian zygotic genome activation. Sci Adv, 8:eabn4935.
  • Maeso, I., Dunwell, T.L., Wyatt, C.D.R., Marlétaz, F., Veto, B., Bernal, J.A., Quah, S., Irimia, M., Holland, P.W.H. (2016). Evolutionary origin and functional divergence of totipotent cell homeobox genes in eutherian mammals. BMC Biology, 14:45.