A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation

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 ac...

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Autores: Wyatt, Christopher Douglas Robert, 1988-, Pernaute, Barbara, Gohr, André, Miret-Cuesta, Marta, Goyeneche, Lucia, Rovira, Quirze, Salzer, Marion C., Boke, Elvan, Bogdanovic, Ozren, Bonnal, Sophie, Irimia Martínez, Manuel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/53342
Acceso en línea:http://hdl.handle.net/10230/53342
http://dx.doi.org/10.1126/sciadv.abn4935
Access Level:acceso abierto
Palabra clave:Genètica
Genòmica
Embriologia
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spelling A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activationWyatt, Christopher Douglas Robert, 1988-Pernaute, BarbaraGohr, AndréMiret-Cuesta, MartaGoyeneche, LuciaRovira, QuirzeSalzer, Marion C.Boke, ElvanBogdanovic, OzrenBonnal, SophieIrimia Martínez, ManuelGenèticaGenòmicaEmbriologiaTransition 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.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)American Association for the Advancement of Science (AAAS)202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/53342http://dx.doi.org/10.1126/sciadv.abn4935reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésinfo:eu-repo/grantAgreement/EC/H2020/656843info:eu-repo/grantAgreement/ES/1PE/BFU2014-55076-Pinfo:eu-repo/grantAgreement/ES/2PE/BFU2017-89201-P© 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 citedhttps://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/533422026-06-12T07:21:37Z
dc.title.none.fl_str_mv A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation
title A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation
spellingShingle A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation
Wyatt, Christopher Douglas Robert, 1988-
Genètica
Genòmica
Embriologia
title_short A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation
title_full A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation
title_fullStr A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation
title_full_unstemmed A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation
title_sort A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation
dc.creator.none.fl_str_mv Wyatt, Christopher Douglas Robert, 1988-
Pernaute, Barbara
Gohr, André
Miret-Cuesta, Marta
Goyeneche, Lucia
Rovira, Quirze
Salzer, Marion C.
Boke, Elvan
Bogdanovic, Ozren
Bonnal, Sophie
Irimia Martínez, Manuel
author Wyatt, Christopher Douglas Robert, 1988-
author_facet Wyatt, Christopher Douglas Robert, 1988-
Pernaute, Barbara
Gohr, André
Miret-Cuesta, Marta
Goyeneche, Lucia
Rovira, Quirze
Salzer, Marion C.
Boke, Elvan
Bogdanovic, Ozren
Bonnal, Sophie
Irimia Martínez, Manuel
author_role author
author2 Pernaute, Barbara
Gohr, André
Miret-Cuesta, Marta
Goyeneche, Lucia
Rovira, Quirze
Salzer, Marion C.
Boke, Elvan
Bogdanovic, Ozren
Bonnal, Sophie
Irimia Martínez, Manuel
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Genètica
Genòmica
Embriologia
topic Genètica
Genòmica
Embriologia
description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/53342
http://dx.doi.org/10.1126/sciadv.abn4935
url http://hdl.handle.net/10230/53342
http://dx.doi.org/10.1126/sciadv.abn4935
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/EC/H2020/656843
info:eu-repo/grantAgreement/ES/1PE/BFU2014-55076-P
info:eu-repo/grantAgreement/ES/2PE/BFU2017-89201-P
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for the Advancement of Science (AAAS)
publisher.none.fl_str_mv American Association for the Advancement of Science (AAAS)
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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