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Review
. 2017 Aug 21;42(4):316-332.
doi: 10.1016/j.devcel.2017.07.026.

Zygotic Genome Activation in Vertebrates

David Jukam  1 , S Ali M Shariati  1 , Jan M Skotheim  2
Affiliations
Review

Zygotic Genome Activation in Vertebrates

David Jukam et al. Dev Cell. .

Abstract

The first major developmental transition in vertebrate embryos is the maternal-to-zygotic transition (MZT) when maternal mRNAs are degraded and zygotic transcription begins. During the MZT, the embryo takes charge of gene expression to control cell differentiation and further development. This spectacular organismal transition requires nuclear reprogramming and the initiation of RNAPII at thousands of promoters. Zygotic genome activation (ZGA) is mechanistically coordinated with other embryonic events, including changes in the cell cycle, chromatin state, and nuclear-to-cytoplasmic component ratios. Here, we review progress in understanding vertebrate ZGA dynamics in frogs, fish, mice, and humans to explore differences and emphasize common features.

Keywords: early vertebrate development; maternal-to-zygotic transition; nuclear-to-cytoplasm ratio; zygotic genome activation.

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Figures

Figure 1
Figure 1. Timing of transcriptional onset and early embryonic events varies in vertebrates
Evolutionary distance, embryo morphology, cell division timing and number in pre-gastrulation development for zebrafish (Danio rerio), frog (Xenopus laevis), mouse (Mus musculus), and human (Homo sapiens). X. laevis and X. tropicalis have broadly similar activation timing with respect to cell division number (Yanai et al., 2011). Purple shading density illustrates amount of zygotic transcription. In the fast developing species, fish and frog, cell divisions are rapid until the mid-blastula transition at the 10th and 12th cycles. In slow developing species, the initial divisions take place over days. Divisions ‘2’ and ‘2*’ refer to the two asynchronous divisions in the 2nd cleavage cycle. Xenopus embryo images adapted from (Nieuwkoop and Faber, 1994); Danio rerio embryo images were reproduced from (Kimmel et al., 1995) with permission (John Wiley and Sons).
Figure 2
Figure 2. Initiation of embryonic transcription is difficult to detect
Several factors influence the total transcription of a specific gene in embryos. (A) When a gene is activated after fertilization, the number of transcripts per gene (i.e., per copy of the genome) is likely linearly increasing (purple) or constant (green). (B) In addition, the number of copies of the genome per embryo is doubling with each cell division. Embryos exhibit an exponential increase in genome copies per unit time during cleavage divisions. (C) Total transcription—and total mRNA production—for a given gene is related to the product of the transcription per genome and the number of genomes. The total mRNA per embryo may thus increase exponentially or even hyper-exponentially in the first hours after activation. The more sensitive the method, the earlier one expects to detect zygotic transcription as indicated by times t1, t2, and t3. Yet, even with a dramatic increase in assay sensitivity (2-fold and 10-fold increases are shown), it may be difficult to detect the earliest transcription when assaying total embryo RNA (red box).
Figure 3
Figure 3. Nuclear-to-cytoplasmic (N/C) ratio-based models for determining the timing of early developmental events
The numerator in the N/C model refers either to nuclear volume or some other nuclear component such as DNA. (A–C) Frog ZGA is regulated, in part, by the N/C ratio. (A) Cell size (i.e., volume) decreases by half with each division in an embryo of constant volume. (B) The ratio of nuclear volume to cytoplasmic volume increases through the mid-blastula transition and may control transcription through an unknown mechanism. Data re-plotted from (Jevtić and Levy, 2015). (C) The ratio of DNA-to-cytoplasm may be encoded by the ratio of DNA-to-histones as histone concentration is constant before the MBT. (D) Cartoon illustrates how a histone titration model may control transcription. (E) In mouse embryos, cell size decreases by half with each division before implantation (top row). N/C ratio may control compaction, where the embryo transitions from a loosely connected group of spherical cells to a tight mass without gaps between cells due to increased cell-to-cell contacts. (bottom row) Removal of ~50% of zygote cytoplasm induces compaction one cell cycle earlier (Lee et al., 2001). Zygote pronuclei are in red and blue; embryonic nuclei are in purple.
Figure 4
Figure 4. Activator-accumulation model for determining the timing of zygotic transcription
Upon fertilization, maternal proteins are deposited and RNA translation is initiated, which triggers the accumulation of transcriptional activators (e.g., TF1). Once this transcription factor reaches a critical concentration (dotted line in graph), specific zygotic target genes initiate transcription. Differential timing of transcriptional activation can arise when the product of an early target gene affects subsequent transcriptional events (e.g., TF2). Transcriptional activation may be negatively regulated by site-specific repressors, competing chromatin components, or rate-limiting cofactors. Importantly, if transcription initiation depends solely on transcription factor concentration, the timing of the earliest transcription events may be independent of ploidy.
Figure 5
Figure 5. Chromatin state dynamics in early mouse embryos
Schematic of changes in chromatin state after fertilization in mouse. Time points shown are the 1-cell zygote, 2-cell stage, and 4- to 8-cell stage. Gene expression begins in pronuclei of the 1-cell zygote and increases through the 2-, 4-, and 8-cell stages. DNA methylation (5mC) decreases sharply on paternal alleles by both active and passive mechanisms, and decreases gradually on maternal alleles largely by passive mechanisms such as dilution by replication. H3K4me3 is present in broad (>10kb) non-canonical domains in the zygote and restricts to promoters during ZGA. H3K27me3 is present distal to promoters and at low levels throughout early embryogenesis, and only becomes present near bivalent promoters in the later blastocyst stages. At the 2-cell stage, local chromatin is accessible in broad domains across repetitive genomic elements, and at gene promoters and transcription end sites. At the 4–8 cell stage, accessible chromatin more resembles that of somatic cells. Topologically associating domains (TADs) are removed after fertilization and gradually reform starting at the 4–8 cell stage. TAD images were reproduced with minor modifications from (Ke et al., 2017) with permission (Elsevier). The sequence of major gene expression phases is driven by different transcription factors and include different types of RNA.
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References

    1. Aanes H, Winata CL, Lin CH, Chen JP, Srinivasan KG, Lee SGP, Lim AYM, Hajan HS, Collas P, Bourque G, et al. Zebrafish mRNA sequencing deciphers novelties in transcriptome dynamics during maternal to zygotic transition. Genome Res. 2011;21:1328–1338. - PMC - PubMed
    1. Abbassi L, Malki S, Cockburn K, Macaulay A, Robert C, Rossant J, Clarke HJ. Multiple Mechanisms Cooperate to Constitutively Exclude the Transcriptional Co-Activator YAP from the Nucleus During Murine Oogenesis. Biol Reprod. 2016;94:102. - PMC - PubMed
    1. Abe K-I, Yamamoto R, Franke V, Cao M, Suzuki Y, Suzuki MG, Vlahovicek K, Svoboda P, Schultz RM, Aoki F. The first murine zygotic transcription is promiscuous and uncoupled from splicing and 3′ processing. Embo J. 2015;34:1523–1537. - PMC - PubMed
    1. Aiken CEM, Swoboda PPL, Skepper JN, Johnson MH. The direct measurement of embryogenic volume and nucleo-cytoplasmic ratio during mouse pre-implantation development. Reproduction. 2004;128:527–535. - PubMed
    1. Akkers RC, van Heeringen SJ, Jacobi UG, Janssen-Megens EM, Françoijs KJ, Stunnenberg HG, Veenstra GJC. A hierarchy of H3K4me3 and H3K27me3 acquisition in spatial gene regulation in Xenopus embryos. Dev Cell. 2009;17:425–434. - PMC - PubMed

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