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Review
. 2014:30:581-613.
doi: 10.1146/annurev-cellbio-100913-013027. Epub 2014 Aug 11.

Zygotic genome activation during the maternal-to-zygotic transition

Miler T Lee  1 , Ashley R Bonneau, Antonio J Giraldez
Affiliations
Review

Zygotic genome activation during the maternal-to-zygotic transition

Miler T Lee et al. Annu Rev Cell Dev Biol. 2014.

Abstract

Embryogenesis depends on a highly coordinated cascade of genetically encoded events. In animals, maternal factors contributed by the egg cytoplasm initially control development, whereas the zygotic nuclear genome is quiescent. Subsequently, the genome is activated, embryonic gene products are mobilized, and maternal factors are cleared. This transfer of developmental control is called the maternal-to-zygotic transition (MZT). In this review, we discuss recent advances toward understanding the scope, timing, and mechanisms that underlie zygotic genome activation at the MZT in animals. We describe high-throughput techniques to measure the embryonic transcriptome and explore how regulation of the cell cycle, chromatin, and transcription factors together elicits specific patterns of embryonic gene expression. Finally, we illustrate the interplay between zygotic transcription and maternal clearance and show how these two activities combine to reprogram two terminally differentiated gametes into a totipotent embryo.

Keywords: cellular reprogramming; embryogenesis; maternal clearance; pioneer factors; pluripotency.

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Figures

Figure 1
Figure 1. Timing of zygotic genome activation across various model organisms
Curves illustrate cumulative increases in zygotic gene expression as development progresses. In mouse, a minor wave of transcription during the first cell cycle is followed by a second wave during cycle 2. C. elegans divisions are asynchronous, with transcription detected by 4 cells. Zygotic transcription in Xenopus, zebrafish and D. melanogaster is detected several cell cycles later, and increases rapidly. Approximate times post fertilization are indicated.
Figure 2
Figure 2. Identification of de novo zygotic transcription
(a) In the early embryo, the maternal contribution (red) represents the majority of the transcripts present. This can mask the relatively small amount of de novo zygotic transcription (blue) and lead to detection difficulties. Experimental techniques that (b) enrich or (c) deplete the signal from zygotic RNAs relative to the maternal contribution can be used to identify the genes that are de novo activated. (d) Subtractive hybridization employs biotinylated (orange) antisense oligos constructed from oocyte cDNA libraries (purple) to selectively deplete complementary maternal transcripts. (e) De novo transcribed mRNAs can be labeled using the nucleoside analog 4-thiouridine (4SU) (green) and pulled down by biotinylation (orange). (f-g) Zygotic transcripts can be identified by unique properties present only in the zygotic form such as the presence of (f) the paternal genotype or (g) introns from pre-mRNAs, which should not be present in mature maternal mRNAs. (h) Transcription can be globally inhibited using chemicals such as a-amanitin. (i) Chromosomal deletion mutants remove the zygotic contribution for genes that fall within the deletion and can be used to identify genes that require both maternal and zygotic expression to reach wild type levels.
Figure 3
Figure 3. General models for ZGA
(a-c) Schematics illustrating the relationship between maternal factors and the zygotic genome as cells divide. (a) Early during embryogenesis, a maternal repressor (red triangles) prevents zygotic transcription. After several divisions, the repressor is titrated away as the ratio of nuclear material to cytoplasm increases (the nucleocytoplasmic ratio), thus allowing transcription to initiate. (b) Developmental time may be necessary for sufficient levels of an activator to accumulate, e.g., resulting from activated translation of a maternal mRNA. (c) Alternatively, the embryo may already possess transcriptional activators (orange circles) and be transcriptionally competent early, but a threshold amount of DNA template is required for transcription to be detected. (d) All of these general mechanisms could combine to elicit increasing transcription levels over developmental time.
Figure 4
Figure 4. Influence of cell cycle on zygotic gene transcription
(a) In some species, early cleavage stages progress through mitosis (M) and DNA synthesis (S) phases with little to no gap phases (G1 and G2). As the embryo divides, maternal DNA replication factors -- Cut5, RecQ4, Treslin and Drf1 in Xenopus (Xen), and Twine in D. melanogaster (Dm) -- are titrated away as the nucleocytoplasmic ratio increases, resulting in cell cycle lengthening. (b) Rapid cell cycles may be incompatible with transcription of longer genes, resulting in failed or abortive RNA polymerase engagement. Longer cell cycles would allow more time for elongation and the accumulation of zygotic transcripts. (c) However, rapid cell cycles do not appear to be prohibitive for transcription of short genes.
Figure 5
Figure 5. Modes of chromatin regulation and establishing competency for zygotic gene activation
(a) Gamete-specific repressive histone variants are replaced with zygotic variants after fertilization, which often bear permissive modifications. (b) Selective post-transcriptional modifications of histone tails are acquired during the MZT, including activating H3K4me3 and repressing H3K27me3 over gene promoters. Some promoters are marked bivalently (both H3K4me3 and H3K27me3), indicating a poised transcriptional state. (c) The organization of nucleosomes around gene promoters is associated with transcriptional competence. Ordered arrays of nucleosomes (labeled +1, +2, +3) form during ZGA around both active promoters and promoters driving later developmental expression. (d) Transcription start site (TSS) utilization on embryonic genes shifts from oocyte-specific A/T-rich regions to G/C-rich sequences. (e) DNA methylation, which is associated with repression, is selectively applied during the MZT in a manner that matches the sperm methylation pattern. (f) Widespread compacted chromatin in the early embryo is thought to be prohibitive for transcription. Maternal pioneer transcription factors may bind closed chromatin in a sequence-specific manner and induce open chromatin through recruitment of chromatin remodelers, allowing access to gene promoters.
Figure 6
Figure 6. Activation of the zygotic genome and maternal clearance together reprogram the embryo during the MZT
(a) Maternally provided factors (red) activate transcription of zygotic genes (blue) through the action of transcription factors (TFs) that engage the early embryonic genome. In turn, zygotic genes, including microRNAs, direct clearance of maternal RNAs. (b) Failure to activate the zygotic genome by inhibiting maternal TF activity results in stabilization of the maternal program and arrested development. (c) In zebrafish, the TFs Nanog, Pou5f1 and Sox19b are required for widespread zygotic gene expression, which includes miR-430. miR-430, along with other unknown factors, induces clearance of a large subset of maternal RNAs. (d) In D. melanogaster, Zelda plays a similar role, and is responsible for activating miR-309, which in turn mediates maternal clearance. Maternal Smaug activity is also required for maternal clearance, as well as for miR-309 expression through an unknown intermediate.
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