Following fertilization, the two specified gametes must unite to create an entirely new organism. The genome is initially transcriptionally quiescent, allowing the zygote to be reprogrammed into a totipotent state. Gradually, the genome is activated through a process known as the maternal-to-zygotic transition, which enables zygotic gene products to replace the maternal supply that initiated development. This essential transition has been broadly characterized through decades of research in several model organisms. However, we still lack a full mechanistic understanding of how genome activation is executed and how this activation relates to the reprogramming of the zygotic chromatin architecture. Recent work highlights the central role of transcriptional activators and suggests that these factors may coordinate transcriptional activation with other developmental changes.
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Gurdon, J. B. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. Development 10, 622–640 (1962).
Campbell, K. H. S., McWhir, J., Ritchie, W. A. & Wilmut, I. Sheep cloned by nuclear transfer from a cultured cell line. Nature 380, 64–66 (1996).
Newport, J. & Kirschner, M. A major developmental transition in early Xenopus embryos: II. Control of the onset of transcription. Cell 30, 687–696 (1982).
Tadros, W. & Lipshitz, H. D. The maternal-to-zygotic transition: a play in two acts. Development 136, 3033–3042 (2009).
Yartseva, V. & Giraldez, A. J. The maternal-to-zygotic transition during vertebrate development: a model for reprogramming. Curr. Top. Dev. Biol. 113, 191–232 (2015).
Yuan, K., Seller, C. A., Shermoen, A. W. & O’Farrell, P. H. Timing the Drosophila mid-blastula transition: a cell cycle-centered view. Trends Genet. 32, 496–507 (2016).
Bertrand, E. et al. Localization of ASH1 mRNA particles in living yeast. Mol. Cell 2, 437–445 (1998).
Nelles, D. A. et al. Programmable RNA tracking in live cells with CRISPR/Cas9. Cell 165, 488–496 (2016).
Wang, Z., Gerstein, M. & Snyder, M. RNA-Seq: a revolutionary tool for transcriptomics. Nat. Rev. Genet. 10, 57–63 (2009).
Furey, T. S. ChIP–seq and beyond: new and improved methodologies to detect and characterize protein–DNA interactions. Nat. Rev. Genet. 13, 840–852 (2012).
Giresi, P. G., Kim, J., McDaniell, R. M., Iyer, V. R. & Lieb, J. D. FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) isolates active regulatory elements from human chromatin. Genome Res. 17, 877–885 (2007).
Buenrostro, J. D., Wu, B., Chang, H. Y. & Greenleaf, W. J. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109, 21.29.1–21.29.9 (2015).
Belton, J.-M. et al. Hi–C: a comprehensive technique to capture the conformation of genomes. Methods 58, 268–276 (2012).
Gao, L. et al. Chromatin accessibility landscape in human early embryos and its association with evolution. Cell 173, 248–259 (2018). This study profiles chromatin accessibility across early human embryogenesis by sequencing DNase I hypersensitive sites and implicates OCT4 as an activator of ZGA.
Mezger, A. et al. High-throughput chromatin accessibility profiling at single-cell resolution. Nat. Commun. 9, 3647 (2018).
Dahl, J. A. et al. Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition. Nature 537, 548–552 (2016).
Zhang, B. et al. Allelic reprogramming of the histone modification H3K4me3 in early mammalian development. Nature 537, 553–557 (2016).
Liu, X. et al. Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos. Nature 537, 558–562 (2016).
Eckersley-Maslin, M. A., Alda-Catalinas, C. & Reik, W. Dynamics of the epigenetic landscape during the maternal-to-zygotic transition. Nat. Rev. Mol. Cell. Biol. 19, 436–450 (2018).
Xu, Q. & Xie, W. Epigenome in early mammalian development: inheritance, reprogramming and establishment. Trends Cell Biol. 28, 237–253 (2018).
Collart, C. et al. High-resolution analysis of gene activity during the Xenopus mid-blastula transition. Development 141, 1927–1939 (2014).
Harvey, S. A. et al. Identification of the zebrafish maternal and paternal transcriptomes. Development 140, 2703–2710 (2013).
Lott, S. E. et al. Noncanonical compensation of the zygotic X transcription in early Drosophila melanogaster development revealed through single-embryo RNA-Seq. PLOS Biol. 9, e1000590 (2011).
Newport, J. & Kirschner, M. A major developmental transition in early Xenopus embryos: I. characterization and timing of cellular changes at the midblastula stage. Cell 30, 675–686 (1982).
Prioleau, M. N., Huet, J., Sentenac, A. & Mechali, M. Competition between chromatin and transcription complex assembly regulates gene expression during early development. Cell 77, 439–449 (1994).
Dekens, M. P. S., Pelegri, F. J., Maischein, H.-M. & Nusslein-Volhard, C. The maternal-effect gene futile cycle is essential for pronuclear congression and mitotic spindle assembly in the zebrafish zygote. Development 130, 3907–3916 (2003).
Edgar, B. A., Kiehle, C. P. & Schubiger, G. Cell cycle control by the nucleo-cytoplasmic ratio in early Drosophila development. Cell 44, 365–372 (1986).
Lu, X., Li, J. M., Elemento, O., Tavazoie, S. & Wieschaus, E. F. Coupling of zygotic transcription to mitotic control at the Drosophila mid-blastula transition. Development 136, 2101–2110 (2009).
Lee, D. R., Lee, J. E., Yoon, H. S., Roh, S. I. & Kim, M. K. Compaction in preimplantation mouse embryos is regulated by a cytoplasmic regulatory factor that alters between 1- and 2-cell stages in a concentration-dependent manner. J. Exp. Zool. 290, 61–71 (2001).
Guven-Ozkan, T., Nishi, Y., Robertson, S. M. & Lin, R. Global transcriptional repression in C. elegans germline precursors by regulated sequestration of TAF-4. Cell 135, 149–160 (2008).
Veenstra, G. J., Destree, O. H. & Wolffe, A. P. Translation of maternal TATA-binding protein mRNA potentiates basal but not activated transcription in Xenopus embryos at the midblastula transition. Mol. Cell. Biol. 19, 7972–7982 (1999).
Benoit, B. et al. An essential role for the RNA-binding protein Smaug during the Drosophila maternal-to-zygotic transition. Development 136, 923–932 (2009).
Tadros, W. et al. SMAUG is a major regulator of maternal mRNA destabilization in Drosophila and its translation is activated by the PAN GU kinase. Dev. Cell 12, 143–155 (2007).
Lee, M. T. et al. Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition. Nature 503, 360–364 (2013). Using ribosome profiling, the authors identify Pou5f3 (previously Pou5f1), Nanog and Sox2 as the most highly translated transcription factors in the early zebrafish embryo and then show that depletion of these factors together results in a failure to initiate ZGA.
Chan, S. H. et al. Brd4 and P300 regulate zygotic genome activation through histone acetylation. Preprint at bioRxiv https://doi.org/10.1101/369231 (2018).
Harrison, M. M., Botchan, M. R. & Cline, T. W. Grainyhead and Zelda compete for binding to the promoters of the earliest-expressed Drosophila genes. Dev. Biol. 345, 248–255 (2010).
Stancheva, I. & Meehan, R. R. Transient depletion of xDnmt1 leads to premature gene activation in Xenopus embryos. Genes Dev. 14, 313–327 (2000).
Ruzov, A. et al. Kaiso is a genome-wide repressor of transcription that is essential for amphibian development. Development 131, 6185–6194 (2004).
Pritchard, D. K. & Schubiger, G. Activation of transcription in Drosophila embryos is a gradual process mediated chardby the nucleocytoplasmic ratio. Genes Dev. 10, 1131–1142 (1996).
Luo, R. X. & Dean, D. C. Chromatin remodeling and transcriptional regulation. J. Natl Cancer Inst. 91, 1288–1294 (1999).
Amodeo, A. A., Jukam, D., Straight, A. F. & Skotheim, J. M. Histone titration against the genome sets the DNA-to-cytoplasm threshold for the Xenopus midblastula transition. Proc. Natl Acad. Sci. USA 112, E1086–E1095 (2015).
Joseph, S. R. et al. Competition between histone and transcription factor binding regulates the onset of transcription in zebrafish embryos. eL ife 6, e23326 (2017). This study shows a decrease in the concentration of unbound histones in the nuclei of zebrafish embryos that corresponds with ZGA and presents evidence that this decrease permits transcription factors to compete for DNA binding and activate transcription.
Jevtic´, P. & Levy, D. L. Nuclear size scaling during Xenopus early development contributes to midblastula transition timing. Curr. Biol. 25, 45–52 (2015).
Jevtic´, P. & Levy, D. L. Both nuclear size and DNA amount contribute to midblastula transition timing in Xenopus laevis. Sci. Rep. 7, 7908 (2017).
Hahn, S. Structure and mechanism of the RNA polymerase II transcription machinery. Nat. Struct. Mol. Biol. 11, 394–403 (2004).
Gottesfeld, J. M. & Forbes, D. J. Mitotic repression of the transcriptional machinery. Trends Biochem. Sci. 22, 197–202 (1997).
Rothe, M., Pehl, M., Taubert, H. & Jackle, H. Loss of gene function through rapid mitotic cycles in the Drosophila embryo. Nature 359, 156–159 (1992).
Shermoen, A. W. & O’Farrell, P. H. Progression of the cell cycle through mitosis leads to abortion of nascent transcripts. Cell 67, 303–310 (1991).
Heyn, P. et al. The earliest transcribed zygotic genes are short, newly evolved, and different across species. Cell Rep. 6, 285–292 (2014).
De Renzis, S., Elemento, O., Tavazoie, S. & Wieschaus, E. F. Unmasking activation of the zygotic genome using chromosomal deletions in the Drosophila embryo. PLOS Biol. 5, e117 (2007).
Swinburne, I. A. & Silver, P. A. Intron delays and transcriptional timing during development. Dev. Cell 14, 324–330 (2008).
Collart, C., Allen, G. E., Bradshaw, C. R., Smith, J. C. & Zegerman, P. Titration of four replication factors is essential for the Xenopus laevis midblastula transition. Science 341, 893–896 (2013).
Kimelman, D., Kirschner, M. & Scherson, T. The events of the midblastula transition in Xenopus are regulated by changes in the cell cycle. Cell 48, 399–407 (1987).
Farrell, J. A. & O’Farrell, P. H. Mechanism and regulation of Cdc25/Twine protein destruction in embryonic cell-cycle remodeling. Curr. Biol. 23, 118–126 (2013).
Zhang, M., Kothari, P., Mullins, M. & Lampson, M. A. Regulation of zygotic genome activation and DNA damage checkpoint acquisition at the mid-blastula transition. Cell Cycle 13, 3828–3838 (2014).
McCleland, M. L. & O’Farrell, P. H. RNAi of mitotic cyclins in Drosophila uncouples the nuclear and centrosome cycle. Curr. Biol. 18, 245–254 (2008).
Sung, H., Spangenberg, S., Vogt, N. & Großhans, J. Number of nuclear divisions in the Drosophila blastoderm controlled by onset of zygotic transcription. Curr. Biol. 23, 133–138 (2017).
Jiang, C. & Pugh, B. F. Nucleosome positioning and gene regulation: advances through genomics. Nat. Rev. Genet. 10, 161–172 (2009).
Bannister, A. J. & Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 21, 381–395 (2011).
Steger, K. & Balhorn, R. Sperm nuclear protamines: a checkpoint to control sperm chromatin quality. Anat. Histol. Embryol. 47, 273–279 (2018).
Zhou, L. & Dean, J. Reprogramming the genome to totipotency in mouse embryos. Trends Cell Biol. 25, 82–91 (2015).
Li, E., Beard, C. & Jaenisch, R. Role for DNA methylation in genomic imprinting. Nature 366, 362–365 (1993).
Panning, B. X-chromosome inactivation: the molecular basis of silencing. J. Biol. 7, 30 (2008).
Guo, H. et al. The DNA methylation landscape of human early embryos. Nature 511, 606–610 (2014).
Shen, L. et al. Tet3 and DNA replication mediate demethylation of both the maternal and paternal genomes in mouse zygotes. Cell Stem Cell 15, 459–471 (2014).
Messerschmidt, D. M., Knowles, B. B. & Solter, D. DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev. 28, 812–828 (2014).
Veenstra, G. J. C. & Wolffe, A. P. Constitutive genomic methylation during embryonic development of Xenopus. Biochim. Biophys. Acta 1521, 39–44 (2001).
Bogdanovic, O. et al. Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis. Genome Res. 21, 1313–1327 (2011).
Potok, M. E., Nix, D. A., Parnell, T. J. & Cairns, B. R. Reprogramming the maternal zebrafish genome after fertilization to match the paternal methylation pattern. Cell 153, 759–772 (2013).
Jiang, L. et al. Sperm, but not oocyte, DNA methylome is inherited by zebrafish early embryos. Cell 153, 773–784 (2013).
Liu, G., Wang, W., Hu, S., Wang, X. & Zhang, Y. Inherited DNA methylation primes the establishment of accessible chromatin during genome activation. Genome Res. 28, 998–1007 (2018).
Yin, Y. et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 356, eaaj2239 (2017).
Takayama, S. et al. Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity. Genome Res. 24, 821–830 (2014).
Kelly, W. G. Transgenerational epigenetics in the germline cycle of Caenorhabditis elegans. Epigenetics Chromatin 7, 6 (2014).
Li, X.-Y., Harrison, M. M., Villalta, J. E., Kaplan, T. & Eisen, M. B. Establishment of regions of genomic activity during the Drosophila maternal to zygotic transition. eLife 3, e03737 (2014).
Bogdanovic, O. et al. Dynamics of enhancer chromatin signatures mark the transition from pluripotency to cell specification during embryogenesis. Genome Res. 22, 2043–2053 (2012).
Eissenberg, J. C. & Shilatifard, A. Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Dev. Biol. 339, 240–249 (2010).
Vastenhouw, N. L. et al. Chromatin signature of embryonic pluripotency is established during genome activation. Nature 464, 922–926 (2010).
Lindeman, L. C. et al. Prepatterning of developmental gene expression by modified histones before zygotic genome activation. Dev. Cell 21, 993–1004 (2011).
Akkers, R. C. et al. A hierarchy of H3K4me3 and H3K27me3 acquisition in spatial gene regulation in Xenopus embryos. Dev. Cell 17, 425–434 (2009).
Hontelez, S. et al. Embryonic transcription is controlled by maternally defined chromatin state. Nat. Commun. 6, 10148 (2015).
Chen, K. et al. A global change in RNA polymerase II pausing during the Drosophila midblastula transition. eLife 2, e00861 (2013).
Zenk, F. et al. Germ line–inherited H3K27me3 restricts enhancer function during maternal-to-zygotic transition. Science 357, 212–216 (2017).
Gaydos, L. J., Wang, W. & Strome, S. H3K27me and PRC2 transmit a memory of repression across generations and during development. Science 345, 1515–1518 (2014).
Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).
Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).
Zheng, H. et al. Resetting epigenetic memory by reprogramming of histone modifications in mammals. Mol. Cell 63, 1066–1079 (2016).
Weber, C. M. & Henikoff, S. Histone variants: dynamic punctuation in transcription. Genes Dev. 28, 672–682 (2014).
Whittle, C. M. et al. The genomic distribution and function of histone variant HTZ-1 during C. elegans embryogenesis. PLOS Genet. 4, e1000187 (2008).
Lin, C.-J., Conti, M. & Ramalho-Santos, M. Histone variant H3.3 maintains a decondensed chromatin state essential for mouse preimplantation development. Development 140, 3624–3634 (2013).
Yang, P., Wu, W. & Macfarlan, T. S. Maternal histone variants and their chaperones promote paternal genome activation and boost somatic cell reprogramming. Bioessays 37, 52–59 (2015).
Gaume, X. & Torres-Padilla, M.-E. Regulation of reprogramming and cellular plasticity through histone exchange and histone variant incorporation. Cold Spring Harb. Symp. Quant. Biol. 80, 165–175 (2015).
Perez-Montero, S., Carbonell, A., Moran, T., Vaquero, A. & Azorin, F. The embryonic linker histone H1 variant of Drosophila, dBigH1, regulates zygotic genome activation. Dev. Cell 26, 578–590 (2013).
Smith, R. C., Dworkin-Rastl, E. & Dworkin, M. B. Expression of a histone H1-like protein is restricted to early Xenopus development. Genes Dev. 2, 1284–1295 (1988).
Fu, G. et al. Mouse oocytes and early embryos express multiple histone H1 subtypes1. Biol. Reprod. 68, 1569–1576 (2003).
Murphy, P. J., Wu, S. F., James, C. R., Wike, C. L. & Cairns, B. R. Placeholder nucleosomes underlie germline-to-embryo DNA methylation reprogramming. Cell 172, 993–1006 (2018).
Zhang, Y. et al. Canonical nucleosome organization at promoters forms during genome activation. Genome Res. 24, 260–266 (2014).
Blythe, S. A. & Wieschaus, E. F. Establishment and maintenance of heritable chromatin structure during early Drosophila embryogenesis. eLife 5, e20148 (2016).
Lu, F. et al. Establishing chromatin regulatory landscape during mouse preimplantation development. Cell 165, 1375–1388 (2016).
Wu, J. et al. The landscape of accessible chromatin in mammalian preimplantation embryos. Nature 534, 652–657 (2016).
Li, L. et al. Single-cell multi-omics sequencing of human early embryos. Nat. Cell Biol. 20, 847–858 (2018).
Wu, J. et al. Chromatin analysis in human early development reveals epigenetic transition during ZGA. Nature 557, 256–260 (2018).
Svoboda, P. et al. RNAi and expression of retrotransposons MuERV-L and IAP in preimplantation mouse embryos. Dev. Biol. 269, 276–285 (2004).
Jachowicz, J. W. et al. LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nat. Genet. 49, 1502–1510 (2017).
Macfarlan, T. S. et al. Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature 487, 57–63 (2012).
Ishiuchi, T. et al. Early embryonic-like cells are induced by downregulating replication-dependent chromatin assembly. Nat. Struct. Mol. Biol. 22, 662–671 (2015).
Dixon, J. R., Gorkin, D. U. & Ren, B. Chromatin domains: the unit of chromosome organization. Mol. Cell 62, 668–680 (2016).
Bonev, B. & Cavalli, G. Organization and function of the 3D genome. Nat. Rev. Genet. 17, 661–678 (2016).
Dekker, J. & Mirny, L. The 3D genome as moderator of chromosomal communication. Cell 164, 1110–1121 (2016).
Hug, C. B. & Vaquerizas, J. M. The birth of the 3D genome during early embryonic development. Trends Genet. 34, P903–P914 (2018).
Hug, C. B., Grimaldi, A. G., Kruse, K. & Vaquerizas, J. M. Chromatin architecture emerges during zygotic genome activation independent of transcription. Cell 169, 216–228 (2017). This paper details the first profile of chromatin conformation changes in the early embryo during the MZT and demonstrates that TAD boundaries are established in concert with ZGA in Drosophila melanogaster.
Ogiyama, Y., Schuettengruber, B., Papadopoulos, G. L., Chang, J.-M. & Cavalli, G. Polycomb-dependent chromatin looping contributes to gene silencing during Drosophila development. Mol. Cell 71, 73–88 (2018).
Ke, Y. et al. 3D chromatin structures of mature gametes and structural reprogramming during mammalian embryogenesis. Cell 170, 367–381 (2017).
Du, Z. et al. Allelic reprogramming of 3D chromatin architecture during early mammalian development. Nature 547, 232–235 (2017).
Kaaij, L. J. T., van der Weide, R. H., Ketting, R. F. & de Wit, E. Systemic loss and gain of chromatin architecture throughout zebrafish development. Cell Rep. 24, 1–10 (2018).
Liang, H.-L. et al. The zinc-finger protein Zelda is a key activator of the early zygotic genome in Drosophila. Nature 456, 400–403 (2008). This paper shows that Zelda is an essential factor for ZGA in Drosophila melanogaster and in so doing identifies the first major activator of the zygotic genome of any species.
Harrison, M. M., Li, X.-Y., Kaplan, T., Botchan, M. R. & Eisen, M. B. Zelda binding in the early Drosophila melanogaster embryo marks regions subsequently activated at the maternal-to-zygotic transition. PLOS Genet. 7, e1002266 (2011).
Nien, C. Y. et al. Temporal coordination of gene networks by Zelda in the early Drosophila embryo. PLOS Genet. 7, e1002339 (2011).
Ribeiro, L. et al. Evolution and multiple roles of the Pancrustacea specific transcription factor zelda in insects. PLOS Genet. 13, e1006868 (2017).
Leichsenring, M., Maes, J., Mossner, R., Driever, W. & Onichtchouk, D. Pou5f1 transcription factor controls zygotic gene activation in vertebrates. Science 341, 1005–1009 (2013). The authors demonstrate that Pou5f3 is bound to chromatin before the onset of zygotic transcription and is instrumental in activating early gene expression.
Takahashi, K. & Yamanaka, S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat. Rev. Mol. Cell. Biol. 17, 183–193 (2016).
Le Bin, G. C. et al. Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst. Development 141, 1001–1010 (2014).
Hendrickson, P. G. et al. Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat. Genet. 49, 925–934 (2017).
De Iaco, A. et al. DUX-family transcription factors regulate zygotic genome activation in placental mammals. Nat. Genet. 49, 941–945 (2017). The studies in references 123 and 124 identify the DUX transcription factors as regulators of mammalian ZGA and support this conclusion by manipulating DUX4 and/or DUX levels in mouse embryos and cell lines.
Whiddon, J. L., Langford, A. T., Wong, C.-J., Zhong, J. W. & Tapscott, S. J. Conservation and innovation in the DUX4-family gene network. Nat. Genet. 49, 935–940 (2017).
Schulz, K. N. et al. Zelda is differentially required for chromatin accessibility, transcription factor binding, and gene expression in the early Drosophila embryo. Genome Res. 25, 1715–1726 (2015).
Sun, Y. et al. Zelda overcomes the high intrinsic nucleosome barrier at enhancers during Drosophila zygotic genome activation. Genome Res. 25, 1703–1714 (2015). The studies in references 126 and 127 demonstrate that Zelda possesses an essential characteristic of pioneer transcription factors, the ability to establish or maintain regions of accessible chromatin.
Veil, M., Yampolsky, L., Gruening, B. & Onichtchouk, D. Pou5f3, SoxB1 and Nanog remodel chromatin on high nucleosome affinity regions at zygotic genome activation. Preprint at bioRxiv https://doi.org/10.1101/344168 (2018).
Oldfield, A. J. et al. Histone-fold domain protein NF-Y promotes chromatin accessibility for cell type-specific master transcription factors. Mol. Cell 55, 708–722 (2014).
Nardini, M. et al. Sequence-specific transcription factor NF-Y displays histone-like DNA binding and H2B-like ubiquitination. Cell 152, 132–143 (2013).
Coustry, F., Hu, Q., de Crombrugghe, B. & Maity, S. N. CBF/NF-Y functions both in nucleosomal disruption and transcription activation of the chromatin-assembled topoisomerase IIα promoter. J. Biol. Chem. 276, 40621–40630 (2001).
Choi, S. H. et al. DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes. Nucleic Acids Res. 44, 5161–5173 (2016).
Soufi, A., Donahue, G. & Zaret, K. S. Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell 151, 994–1004 (2012).
Soufi, A. et al. Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell 161, 555–568 (2015).
Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011).
King, H. W. & Klose, R. J. The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells. eL ife 6, e22631 (2017).
Stadhouders, R. et al. Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming. Nat. Genet. 50, 238–249 (2018).
Meier, M. et al. Cohesin facilitates zygotic genome activation in zebrafish. Development 145, dev156521 (2018).
Mir, M. et al. Dense Bicoid hubs accentuate binding along the morphogen gradient. Genes Dev. 31, 1784–1794 (2017).
Liu, Z. et al. 3D imaging of Sox2 enhancer clusters in embryonic stem cells. eL ife 3, e04236 (2014).
Hamm, D. C., Bondra, E. R. & Harrison, M. M. Transcriptional activation is a conserved feature of the early embryonic factor Zelda that requires a cluster of four zinc fingers for DNA binding and a low-complexity activation domain. J. Biol. Chem. 290, 3508–3518 (2015).
Mir, M. et al. Dynamic multifactor hubs interact transiently with sites of active transcription in Drosophila embryos. eLife (in the press).
Dufourt, J. et al. Temporal control of gene expression by the pioneer factor Zelda through transient interactions in hubs. Nat Commun. 9, 5194 (2018).
Staudt, N., Fellert, S., Chung, H.-R., Jäckle, H. & Vorbrüggen, G. Mutations of the Drosophila zinc finger-encoding gene vielfältig impair mitotic cell divisions and cause improper chromosome segregation. Mol. Biol. Cell 17, 2356–2365 (2006).
Hamm, D. C. et al. A conserved maternal-specific repressive domain in Zelda revealed by Cas9-mediated mutagenesis in Drosophila melanogaster. PLOS Genet. 13, e1007120 (2017).
Onichtchouk, D. & Driever, W. Zygotic genome activators, developmental timing, and pluripotency. Curr. Top. Dev. Biol. 116, 273–297 (2016).
Lunde, K., Belting, H.-G. & Driever, W. Zebrafish pou5f1/pou2, homolog of mammalian Oct4, functions in the endoderm specification cascade. Curr. Biol. 14, 48–55 (2004).
Onichtchouk, D. et al. Oct4/Pou5f1 controls tissue-specific repressors in early zebrafish embryo. J. Stem Cells Regen. Med. 6, 82 (2010).
Veil, M. et al. Maternal Nanog is required for zebrafish embryo architecture and for cell viability during gastrulation. Development 145, dev155366 (2018).
Gagnon, J. A., Obbad, K. & Schier, A. F. The primary role of zebrafish nanog is in extra-embryonic tissue. Development 145, dev147793 (2018).
Vanderplanck, C. et al. The FSHD atrophic myotube phenotype is caused by DUX4 expression. PLOS ONE 6, e26820 (2011).
Lemmers, R. J. L. F. et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 329, 1650–1653 (2010).
Geng, L. N. et al. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev. Cell 22, 38–51 (2012).
Young, J. M. et al. DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis. PLOS Genet. 9, e1003947 (2013).
Iglesias, J. M., Gumuzio, J. & Martin, A. G. Linking pluripotency reprogramming and cancer. Stem Cells Transl Med. 6, 335–339 (2017).
Liu, A., Yu, X. & Liu, S. Pluripotency transcription factors and cancer stem cells: small genes make a big difference. Chin. J. Cancer 32, 483–487 (2013).
Adamson, E. D. & Woodland, H. R. Histone synthesis in early amphibian development: histone and DNA syntheses are not co-ordinated. J. Mol. Biol. 88, 263–285 (1974).
Wang, Y. et al. Unique molecular events during reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) at naïve state. eLife 7, e29518 (2018).
Deng, W. et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell 158, 849–860 (2014).
Henikoff, S. & Shilatifard, A. Histone modification: cause or cog? Trends Genet. 27, 389–396 (2011).
Bazzini, A. A. et al. Codon identity regulates mRNA stability and translation efficiency during the maternal-to-zygotic transition. EMBO J. 35, 2087–2103 (2016).
Mishima, Y. & Tomari, Y. Codon usage and 3′ UTR length determine maternal mRNA stability in zebrafish. Mol. Cell 61, 874–885 (2016).
Ivanova, I. et al. The RNA m6A reader YTHDF2 is essential for the post-transcriptional regulation of the maternal transcriptome and oocyte competence. Mol. Cell 67, 1059–1067 (2017).
Zhao, B. S. et al. m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature 542, 475–478 (2017).
Edgar, B. A. & Datar, S. A. Zygotic degradation of two maternal Cdc25 mRNAs terminates Drosophila’s early cell cycle program. Genes Dev. 10, 1966–1977 (1996).
Bashirullah, A. et al. Joint action of two RNA degradation pathways controls the timing of maternal transcript elimination at the midblastula transition in Drosophila melanogaster. EMBO J. 18, 2610–2620 (1999).
Hamatani, T., Carter, M. G., Sharov, A. A. & Ko, M. S. H. Dynamics of global gene expression changes during mouse preimplantation development. Dev. Cell 6, 117–131 (2004).
Giraldez, A. J. et al. Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science 312, 75–79 (2006).
Lund, E., Liu, M., Hartley, R. S., Sheets, M. D. & Dahlberg, J. E. Deadenylation of maternal mRNAs mediated by miR-427 in Xenopus laevis embryos. RNA 15, 2351–2363 (2009).
Bushati, N., Stark, A., Brennecke, J. & Cohen, S. M. Temporal reciprocity of mi-RNAs and their targets during the maternal-to-zygotic transition in Drosophila. Curr. Biol. 18, 501–506 (2008).
Yan, L. et al. Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells. Nat. Struct. Mol. Biol. 20, 1131–1139 (2013).
Briggs, J. A. et al. The dynamics of gene expression in vertebrate embryogenesis at single-cell resolution. Science 360, eaar5780 (2018).
Farrell, J. A. et al. Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis. Science 360, eaar3131 (2018).
Wagner, D. E. et al. Single-cell mapping of gene expression landscapes and lineage in the zebrafish embryo. Science 360, 981–987 (2018).
Sawant, A. A. et al. A versatile toolbox for posttranscriptional chemical labeling and imaging of RNA. Nucleic Acids Res. 44, e16 (2016).
Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).
Mir, M. et al. Single molecule imaging in live embryos using lattice light-sheet microscopy. Methods Mol. Biol. 1814, 541–559 (2018).
Bothma, J. P., Norstad, M. R., Alamos, S. & Garcia, H. G. LlamaTags: a versatile tool to image transcription factor dynamics in live embryos. Cell 173, 1810–1822 (2018).
Campbell, P. D., Chao, J. A., Singer, R. H. & Marlow, F. L. Dynamic visualization of transcription and RNA subcellular localization in zebrafish. Development 142, 1368–1374 (2015).
Ferraro, T. et al. Transcriptional memory in the Drosophila embryo. Curr. Biol. 26, 212–218 (2016).
Bothma, J. P. et al. Dynamic regulation of eve stripe 2 expression reveals transcriptional bursts in living Drosophila embryos. Proc. Natl Acad. Sci. USA 111, 10598–10603 (2014).
Senecal, A. et al. Transcription factors modulate c-Fos transcriptional bursts. Cell Rep. 8, 75–83 (2014).
Garcia, H. G., Tikhonov, M., Lin, A. & Gregor, T. Quantitative imaging of transcription in living Drosophila embryos links polymerase activity to patterning. Curr. Biol. 23, 2140–2145 (2013).
Deng, W., Shi, X., Tjian, R., Lionnet, T. & Singer, R. H. CASFISH: CRISPR/Cas9-mediated in situ labeling of genomic loci in fixed cells. Proc. Natl Acad. Sci. USA 112, 11870–11875 (2015).
Qin, P. et al. Live cell imaging of low- and non-repetitive chromosome loci using CRISPR-Cas9. Nat. Commun. 8, 14725 (2017).
O’Connell, M. R. et al. Programmable RNA recognition and cleavage by CRISPR/Cas9. Nature 516, 263–266 (2014).
Gualdi, R. et al. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev. 10, 1670–1682 (1996).
Lee, C. S., Friedman, J. R., Fulmer, J. T. & Kaestner, K. H. The initiation of liver development is dependent on Foxa transcription factors. Nature 435, 944–947 (2005).
Zaret, K. S. & Mango, S. E. Pioneer transcription factors, chromatin dynamics, and cell fate control. Curr. Opin. Genet. Dev. 37, 76–81 (2016).
Blythe, S. A., Cha, S.-W., Tadjuidje, E., Heasman, J. & Klein, P. S. β-Catenin primes organizer gene expression by recruiting a histone H3 arginine 8 methyltransferase, Prmt2. Dev. Cell 19, 220–231 (2010).
Cirillo, L. A. et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol. Cell 9, 279–289 (2002).
Clark, K. L., Halay, E. D., Lai, E. & Burley, S. K. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 364, 412–420 (1993).
Taube, J. H., Allton, K., Duncan, S. A., Shen, L. & Barton, M. C. Foxa1 functions as a pioneer transcription factor at transposable elements to activate Afp during differentiation of embryonic stem cells. J. Biol. Chem. 285, 16135–16144 (2010).
Lachnit, M., Kur, E. & Driever, W. Alterations of the cytoskeleton in all three embryonic lineages contribute to the epiboly defect of Pou5f1/Oct4 deficient MZspg zebrafish embryos. Dev. Biol. 315, 1–17 (2008).
Reim, G., Mizoguchi, T., Stainier, D. Y., Kikuchi, Y. & Brand, M. The POU domain protein spg (pou2/Oct4) is essential for endoderm formation in cooperation with the HMG domain protein casanova. Dev. Cell 6, 91–101 (2004).
Reim, G. & Brand, M. Maternal control of vertebrate dorsoventral axis formation and epiboly by the POU domain protein Spg/Pou2/Oct4. Development 133, 2757–2770 (2006).
Okuda, Y., Ogura, E., Kondoh, H. & Kamachi, Y. B1 SOX coordinate cell specification with patterning and morphogenesis in the early zebrafish embryo. PLOS Genet. 6, e1000936 (2010).
Xu, C. et al. Nanog-like regulates endoderm formation through the Mxtx2-Nodal pathway. Dev. Cell 22, 625–638 (2012).
Fogarty, N. M. E. et al. Genome editing reveals a role for OCT4 in human embryogenesis. Nature 550, 67–73 (2017).
The authors thank members of the Harrison laboratory and the reviewers for helpful feedback on the manuscript. K.N.S. was supported in part by the National Institutes of Health (NIH) National Research Service award T32 GM007215. M.M.H. was supported by grant R01GM11694 from the National Institute of General Medical Sciences and a Vallee Scholar Award.
Nature Reviews Genetics thanks B. Cairns, K. Kuznetsova, N. Vastenhouw and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The property of a cell with the capacity to form all the cells of an organism, including extra-embryonic tissues.
Relating to the diploid, fertilized egg cell (zygote) that results from the fusion of an egg and a sperm.
- Germ layers
The three layers of cells (ectoderm, mesoderm and endoderm) that are formed during gastrulation in the early embryo and differentiate to give rise to all the organs and tissues of the body.
The complex of DNA, RNA and protein that makes up the chromosomes of eukaryotes.
- Cleavage divisions
The rapid, modified cell cycles of the early embryo that consist of only M (mitosis) and S (replication) phases and omit the G1 and G2 gap phases. These cycles occur in the absence of cell growth and therefore result in no change in the size of the embryo.
- Nucleocytoplasmic ratio
(N:C ratio). The ratio of the nuclear content to the cytoplasmic content in a cell or embryo.
Refers to an egg that has been fertilized by more than one sperm and thus contains three or more copies of each chromosome.
Characterized by a single set of chromosomes. Most animals have diploid somatic cells (with two paired sets of chromosomes) but produce haploid gametes.
- Compound chromosomes
Chromosomes formed by the attachment of two homologues through a single centromere that are therefore inherited together through mitosis and meiosis. They can be used to generate embryos deficient for an entire chromosome.
Small, basic proteins that are used in the place of histones to help package DNA in the sperm of some species.
The process by which a demethylase enzyme removes a methyl group from a molecule.
- Transposable elements
DNA sequences that can move from one position within the genome to another.
- Topologically associating domains
(TADs). 3D chromosome structures within which DNA regions physically interact with each other more frequently than with regions outside.
A family of endogenous retroviruses expressed in mouse embryos during zygotic genome activation. The human version is known as HERVL.
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Schulz, K.N., Harrison, M.M. Mechanisms regulating zygotic genome activation. Nat Rev Genet 20, 221–234 (2019). https://doi.org/10.1038/s41576-018-0087-x
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