Dynamic changes in maternal‒zygotic transition (MZT) require complex regulation of zygote formation, maternal transcript decay, embryonic genome activation (EGA), and cell cycle progression. Although these changes are well described, some key regulatory factors are still elusive. Sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase, is a versatile driver of MZT via its epigenetic and nonepigenetic substrates. This study focused on the dynamics of SIRT1 in early embryos and its contribution to MZT. A conditional SIRT1-deficient knockout mouse model was used, accompanied by porcine and human embryos. Embryos across mammalian species showed the prominent localization of SIRT1 in the nucleus throughout early embryonic development. Accordingly, SIRT1 interacts with histone H4 on lysine K16 (H4K16) in both mouse and human blastocysts. While maternal SIRT1 is dispensable for MZT, at least one allele of embryonic Sirt1 is required for early embryonic development around the time of EGA. This role of SIRT1 is surprisingly mediated via a transcription-independent mode of action.

1st Faculty of Medicine Institute of Biology and Medical Genetics Charles University Kateřinská 1660 32 121 08 Prague Czech Republic

Faculty of Medicine in Pilsen Biomedical Center Charles University Alej Svobody 76 323 00 Pilsen Czech Republic

Faculty of Medicine in Pilsen Department of Histology and Embryology Charles University Alej Svobody 76 323 00 Pilsen Czech Republic

Faculty of Natural Sciences and Informatics Constantine the Philosopher University in Nitra Nabrezie Mladeze 91 94974 Nitra Slovakia

Institute of Animal Physiology and Genetics of the Czech Academy of Sciences Rumburska 89 277 21 Libechov Czech Republic

Institute of Animal Science Přátelství 815 Uhříněves 104 00 Prague Czech Republic

Laboratory of Genomics and Bioinformatics Institute of Molecular Genetics of the Czech Academy of Sciences Vídeňská 1083 142 20 Prague 4 Czech Republic

Pronatal Sanatorium Na Dlouhé Mezi 12 4 147 00 Prague 4 Czech Republic

Université Paris Saclay Université de Versailles Saint Quentin en Yvelines INRAE BREED Jouy en Josas France

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