The maternal-to-zygotic transition: reprogramming of the cytoplasm and nucleus

Abstract

A fertilized egg is initially transcriptionally silent and relies on maternally provided factors to initiate development. For embryonic development to proceed, the oocyte-inherited cytoplasm and the nuclear chromatin need to be reprogrammed to create a permissive environment for zygotic genome activation (ZGA). During this maternal-to-zygotic transition (MZT), which is conserved in metazoans, transient totipotency is induced and zygotic transcription is initiated to form the blueprint for future development. Recent technological advances have enhanced our understanding of MZT regulation, revealing common themes across species and leading to new fundamental insights about transcription, mRNA decay and translation.

Fig. 1 |. An overview of the maternal-to-zygotic transition (MZT)

a, The maternal-to-zygotic transition (MZT) is a reprogramming of the embryonic cytoplasm and the nucleus. Upon fertilization of an oocyte by the sperm, early development is driven by maternally provided proteins, as well as by newly translated proteins from maternal transcripts. Maternal mRNAs are cleared by maternal factors (maternal decay (M-decay)) or zygotic factors (zygotic decay (Z-decay)). The reprogramming of the nucleus enables zygotic genome activation (ZGA), which results in zygotic transcripts that eventually change the composition of the cytoplasm to be zygotic. b, Timing of ZGA onset in fast-developing and slow-developing embryos is depicted in hours post fertilization and cleavage/nuclear cycle number. The first embryo of each pair denotes the timing of the first reproducible transcription events, whose detection often requires highly specialized or sensitive methods; the second embryo indicates the timing of the large-scale onset of zygotic transcription. These events have traditionally been called ‘minor’ and ‘major’ waves of ZGA, respectively. Recent studies in several species also suggest even earlier transcription events, although many of these may be spurious (Table 1). Note that the timings depicted for Xenopus ZGA are for Xenopus tropicalis; in Xenopus laevis, robust ZGA begins at cleavage cycle 12, at ~5 h post fertilization.

Fig. 2 |. Regulating the stability and translation of maternally deposited transcripts

a, In somatic cells, transcript deadenylation is the rate-limiting step for decay. However, deadenylated transcripts remain stable in oocytes and early embryos due to protective RNA binding proteins (RBPs) and overall low translation levels that protect mRNAs from translation-dependent decay. Cytoplasmic polyadenylation element binding protein (CPEB) represses translation initially, until its later activation by phosphorylation leads to recruitment of a poly(A) polymerase and cytoplasmic polyadenylation of transcripts. Longer poly(A) tails, which better compete for the translation-promoting poly(A)-binding protein PABPC, lead to translational upregulation. Poly(A) tail length and translational efficiency are coupled in pre-gastrulation embryos. b, Model (based on data from zebrafish and Xenopus laevis embryos) depicting how ribosome dormancy affects translation levels in early embryos. Initially, ribosomes are largely repressed by dormancy factors, leading to transcript competition for a limited pool of active ribosomes. Ribosome activation through the removal of dormancy factors leads to translational upregulation and exposes mRNAs to translation-dependent decay. Dormant ribosomes are coloured dark grey; active ribosomes are coloured light grey.

Fig. 3 |. Molecular mechanisms governing maternal transcript clearance

a, Maternal transcript clearance events can be driven by maternally deposited proteins and proteins translated from maternal mRNAs (maternal decay (M-decay)) or zygotically expressed factors such as microRNAs (miRNAs) or proteins (zygotic decay (Z-decay)). b, Translation-dependent (left) and translation-independent (right) mechanisms govern maternal transcript stability and clearance dynamics during the maternal-to-zygotic transition (MZT). Different elements or features of an mRNA transcript and transacting factors that regulate decay during the MZT are shown. Universal mechanisms or regulators used by multiple species are coloured grey. Speciesspecific regulators are highlighted in other colours (Drosophila melanogaster, blue; zebrafish, yellow; Xenopus spp., green; mouse, red) (Table 1). c, Different mechanisms can recruit the CCR4–NOT complex, leading to deadenylation and decay. Translation-independent decay mechanisms include recruitment via Argonaute (Ago)-bound miRNA and TNRC6 or via RNA binding proteins (RBPs) (D. melanogaster Smaug is shown as an example), although miRNAs and RBPs can also directly affect translation independent of decay. Translation-dependent decay mechanisms include recruitment via non-optimal codons and Upf1. Phosphorylated Upf1 recruits CCR4–NOT on long open reading frames (ORFs) but is counteracted by the higher translation rates of shorter ORFs, thereby preventing Upf1-induced deadenylation. BRAT, Brain tumour; CDS, coding sequence; endo-siRNA, endogenous short interfering RNA; m5c, 5-methylcytosine; m6A, N6-methyladenosine; piRNA, Piwi-interacting RNA; UTR, untranslated region.

Fig. 4 |. Transcriptional competency is achieved by nuclear remodelling

Aa, Pioneer transcription factors (PFs) can bind cis-regulatory elements (CREs) on nucleosomal DNA, making them accessible for other factors, such as activators (‘Act’) or repressors (‘Rep’). Ab, Pioneering activity can require cooperative interactions. PF binding sites can be suboptimal (striped CRE) at weakly positioned nucleosomes, requiring increased PF concentration and/or cooperative action. Ac, PFs can act as a ‘regular’ transcription factor (TF) depending on the specific locus. B, Nuclear remodelling on multiple scales. Ba, Global genome architecture, in the form of A (‘active’) and B (‘inactive’) compartments and topologically associating domains (TADs), arises during the maternal-to-zygotic transition (MZT) in most species. Bb, Local chromatin forms enhancer–promoter contacts to initiate zygotic transcription. Bc, At CREs, PFs change the nucleosome landscape, making them accessible to other TFs and chromatin remodellers (CRs). Maternally deposited zygotic genome activation (ZGA)-regulating TFs with demonstrated or suggested pioneering ability in different species are listed (Drosophila melanogaster, blue; zebrafish, yellow; Xenopus spp., green; mouse, red). Bd, Histone tail modifications are also remodelled and form bivalent modifications in some species. Bars represent the timing of acquisition of different marks relative to the onset of ZGA. Histone H3 acetylated at lysine 27 (H3K27ac), mediated by histone acetyltransferases (HATs) p300/CBP, is essential for ZGA. C, Our hypothesized transcription regulation model postulates a central role for acetylated histones: transient promoter–enhancer contacts initiate transcription (step 1); productive transcriptional elongation by RNA polymerase II (Pol II) ‘kicks’ enhancers away from promoters, and acetylated nucleosomes retain enhancer–promoter contact memory (step 2); after histone deacetylase (HDAC)-mediated deacetylation, the transcriptional burst is terminated (step 3); and transcriptional re-initiation requires renewed enhancer–promoter proximity and histone acetylation (step 4). This proposed model will require testing in the future. H3K4me3, histone H3 trimethylated at lysine 4; H3K27me3, histone H3 trimethylated at lysine .

Fig. 5 |. Elapsed developmental time is the key regulator of zygotic genome activation (ZGA) onset timing

a, Wild-type embryos of fast-developing species (zebrafish and Xenopus spp.) initiate zygotic genome activation (ZGA) at a high nuclear-to-cytoplasmic volume ratio (N:C ratio). When the cell cycle is stalled in pre-ZGA zebrafish and Xenopus laevis embryos (by checkpoint kinase 1 (Chk1) overexpression or cycloheximide treatment,,, for example), the N:C ratio remains unchanged; however, ZGA can initiate at a similar developmental time to wild-type embryos, even when at a lower N:C ratio. This suggests that an increased developmental time window is what creates a permissive state for transcription rather than an increased N:C ratio owing to cell division. b, During development, increased translation of transcription factors (TFs) (blue), acetyltransferases (yellow) and other factors (dark grey) prepares the nucleus for ZGA. Additionally, increased nuclear pore complex (NPC) maturation and Importin affinities for TFs regulate the nuclear import of these proteins. The cell cycle duration is tightly coupled to the N:C ratio and maternally deposited histone proteins are diluted with every cell cleavage. Overabundant histones can control ZGA timing by competing with TFs for DNA binding. Early cell cycles in fast-developing species include only S and M phases; as the cell cycle lengthens, G phases are added.