A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation
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- dc.contributor.author Wyatt, Christopher Douglas Robert, 1988-
- dc.contributor.author Pernaute, Barbara
- dc.contributor.author Gohr, André
- dc.contributor.author Miret-Cuesta, Marta
- dc.contributor.author Goyeneche, Lucia
- dc.contributor.author Rovira, Quirze
- dc.contributor.author Salzer, Marion C.
- dc.contributor.author Boke, Elvan
- dc.contributor.author Bogdanovic, Ozren
- dc.contributor.author Bonnal, Sophie
- dc.contributor.author Irimia Martínez, Manuel
- dc.date.accessioned 2022-06-01T08:57:17Z
- dc.date.available 2022-06-01T08:57:17Z
- dc.date.issued 2022
- dc.description.abstract Transition from maternal to embryonic transcriptional control is crucial for embryogenesis. However, alternative splicing regulation during this process remains understudied. Using transcriptomic data from human, mouse, and cow preimplantation development, we show that the stage of zygotic genome activation (ZGA) exhibits the highest levels of exon skipping diversity reported for any cell or tissue type. Much of this exon skipping is temporary, leads to disruptive noncanonical isoforms, and occurs in genes enriched for DNA damage response in the three species. Two core spliceosomal components, Snrpb and Snrpd2, regulate these patterns. These genes have low maternal expression at ZGA and increase sharply thereafter. Microinjection of Snrpb/d2 messenger RNA into mouse zygotes reduces the levels of exon skipping at ZGA and leads to increased p53-mediated DNA damage response. We propose that mammalian embryos undergo an evolutionarily conserved, developmentally programmed splicing failure at ZGA that contributes to the attenuation of cellular responses to DNA damage.
- dc.description.sponsorship This work was funded by the Spanish Ministerio de Ciencia grants BFU2014-55076-P, BFU2017-89201-P and PID2020-115040GB-I00 (M.I.), Marie Skłodowska-Curie actions grant H2020-MSCA-IF-2014_ST-656843 (B.P.), La Caixa PhD fellowship (C.D.R.W.), and “Centro de Excelencia Severo Ochoa 2013-2017” SEV-2012-0208 (CRG-MI)
- dc.format.mimetype application/pdf
- dc.identifier.citation Wyatt CDR, Pernaute B, Gohr A, Miret-Cuesta M, Goyeneche L, Rovira Q et al. A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation. Sci Adv. 2022 Apr 15;8(15):eabn4935. DOI:10.1126/sciadv.abn4935
- dc.identifier.doi http://dx.doi.org/10.1126/sciadv.abn4935
- dc.identifier.issn 2375-2548
- dc.identifier.uri http://hdl.handle.net/10230/53342
- dc.language.iso eng
- dc.publisher American Association for the Advancement of Science (AAAS)
- dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/656843
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-55076-P
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89201-P
- dc.rights © 2022 Christopher D. R. Wyatt et al. Some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri https://creativecommons.org/licenses/by-nc/4.0/
- dc.subject.other Genètica
- dc.subject.other Genòmica
- dc.subject.other Embriologia
- dc.title A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion