Regulation of early embryo development and pluripotency through alternative splicing

Regulation of early embryo development and pluripotency through alternative splicingRegulation of early embryo development and pluripotency through alternative splicing

Current lab members: Marta Miret, Niccolo Arecco.
Former lab members: Bárbara Pernaute, Chris Wyatt, Victoria Rodríguez-Vaello, Thomas Spruce, Lucia-Goyeneche, Quirze Rovira, Mireya Plass.
Funding: Plan Estatal MICINN, Marie Skłodowska-Curie Actions, Boehringer Ingelheim, La Caixa Foundation, CRG.

Understanding how the differentiation potential of the mammalian embryo gets restricted during development is a key question in the embryology and stem cell fields. As with every developmental process, the loss of differentiation potential is expected to be caused by extensive transcriptome remodeling through transcriptional and post-transcriptional regulatory mechanisms. Among the latter, alternative splicing is the most prevalent in mammals, with over 90% of human genes being alternatively spliced. However, little is known regarding its role in modulating pluripotency and cell differentiation. Moreover, the first lineage decision (trophectoderm vs inner cell mass) occurs at the very first stages of development. The trophectoderm will eventually give rise to the placenta, a key mammalian innovation. The aim of this research line is to study the role that alternative splicing plays in these processes.


Exonic-centric view of mouse early development: from zygote to blastocyst (Barbara Pernaute)

So far, our research in these topics have revealed surprising findings in relation to the regulation and function of alternative splicing during the zygotic genome activation (see "Evolution of zygotic genome activation across metazoans"), as well as the neofunctionalization of Mbnl3 during the origin of the placenta. Moreover, we are characterizing the impact of two PanAS events (exons that are alternatively spliced in virtually all cells, generating two co-expressed isoforms; see Tapial 2017) in genes involved in transcriptional regulation and the regulation of alternative splicing during the naive-to-primed pluripotency transition.

In summary, the results obtained in this research line will provide novel insights into how alternative splicing impacts pluripotency and early embryo development. Thus, it will advance our understanding of how genetic networks from multiple regulatory layers control pluripotency and self-renewal in stem cells and in vivo, which is essential for their safe and effective use for therapeutic applications.

Related publications:

  • Spruce, T. †, Plass, M., Gohr, A., Ray, D., Martínez de Lagrán, M., Rot, G., Nóvoa, A., Burguera, D., Permanyer, J., Miret-Cuesta, M., Zheng, H., Swanson, M.S., Morris, Q., Mallo, M., Dierssen, M., Hughes, T.R., Pernaute, B. †, Irimia, M.† (2022). The X-linked splicing regulator MBNL3 has been co-opted to restrict placental growth in eutherians. PLoS Biology, 20(4):e3001615.
  • 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.
  • Han, H.*, Irimia, M.*, Ross P.J., Sung, H.K., Alipanahi, B., David, L., Golipour, A., Gabut, M., Michael, I.P., Nachma, E.N., Wang, E., Trcka, D., Thompson, T., O’Hanlon, D., Slobodeniuc, V., Barbosa-Morais, N.L., Burge, C.B., Moffat, J., Frey, B.J., Nagy, A., Ellis, J., Wrana, J.L, Blencowe, B.J. (2013). MBNL proteins repress embryonic stem-cell-specific alternative splicing and reprogramming. Nature, 498(7453):241-5.