title: Long-Lived Binding of Sox2 to DNA Predicts Cell Fate in the Four-Cell Mouse Embryo.
abstract: Transcription factor (TF) binding to DNA is fundamental for gene regulation. However, it remains unknown how the dynamics of TF-DNA interactions change during cell-fate determination in vivo. Here, we use photo-activatable FCS to quantify TF-DNA binding in single cells of developing mouse embryos. In blastocysts, the TFs Oct4 and Sox2, which control pluripotency, bind DNA more stably in pluripotent than in extraembryonic cells. By contrast, in the four-cell embryo, Sox2 engages in more long-lived interactions than does Oct4. Sox2 long-lived binding varies between blastomeres and is regulated by H3R26 methylation. Live-cell tracking demonstrates that those blastomeres with more long-lived binding contribute more pluripotent progeny, and reducing H3R26 methylation decreases long-lived binding, Sox2 target expression, and pluripotent cell numbers. Therefore, Sox2-DNA binding predicts mammalian cell fate as early as the four-cell stage. More generally, we reveal the dynamic repartitioning of TFs between DNA sites driven by physiological epigenetic changes. VIDEO ABSTRACT.
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: White
authors.affiliation: Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, CONICET, Buenos Aires C1428EHA, Argentina.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Angiolini
authors.affiliation: Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, CONICET, Buenos Aires C1428EHA, Argentina.
authors.forename: Yanina D
authors.initials: YD
authors.lastname: Alvarez
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Gurpreet
authors.initials: G
authors.lastname: Kaur
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Ziqing W
authors.initials: ZW
authors.lastname: Zhao
authors.affiliation: Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, CONICET, Buenos Aires C1428EHA, Argentina.
authors.forename: Esteban
authors.initials: E
authors.lastname: Mocskos
authors.affiliation: Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, CONICET, Buenos Aires C1428EHA, Argentina.
authors.forename: Luciana
authors.initials: L
authors.lastname: Bruno
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bissiere
authors.affiliation: Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, CONICET, Buenos Aires C1428EHA, Argentina. Electronic address: vlevi12@gmail.com.
authors.forename: Valeria
authors.initials: V
authors.lastname: Levi
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore. Electronic address: plachtan@imcb.a-star.edu.sg.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Plachta
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004058:Diffusion; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000032:analysis; D006657:Histones / Q000378:metabolism; D007700:Kinetics; D008745:Methylation; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D013050:Spectrometry, Fluorescence
chemical_list: D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D006657:Histones; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D049452:Green Fluorescent Proteins; D004247:DNA