What defines the maternal transcriptome?

Abstract

In somatic cells, RNA polymerase II (Pol II) transcription initiation starts by the binding of the general transcription factor TFIID, containing the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs), to core promoters. However, in growing oocytes active Pol II transcription is TFIID/TBP-independent, as during oocyte growth TBP is replaced by its vertebrate-specific paralog TBPL2. TBPL2 does not interact with TAFs, but stably associates with TFIIA. The maternal transcriptome is the population of mRNAs produced and stored in the cytoplasm of growing oocytes. After fertilization, maternal mRNAs are inherited by the zygote from the oocyte. As transcription becomes silent after oocyte growth, these mRNAs are the sole source for active protein translation. They will participate to complete the protein pool required for oocyte terminal differentiation, fertilization and initiation of early development, until reactivation of transcription in the embryo, called zygotic genome activation (ZGA). All these events are controlled by an important reshaping of the maternal transcriptome. This procedure combines cytoplasmic readenylation of stored transcripts, allowing their translation, and different waves of mRNA degradation by deadenylation coupled to decapping, to eliminate transcripts coding for proteins that are no longer required. The reshaping ends after ZGA with an almost total clearance of the maternal transcripts. In the past, the murine maternal transcriptome has received little attention but recent progresses have brought new insights into the regulation of maternal mRNA dynamics in the mouse. This review will address past and recent data on the mechanisms associated with maternal transcriptome dynamic in the mouse.

Keywords: RNA decay; RNA polymerase II transcription; TBPL2; early embryo; mouse oocytes; readenylation.

Figure 1.. Establishment and reshaping of the maternal transcriptome in the mouse.

(A) Summary of the folliculogenesis and early development in the mouse. Each follicle (from primordial to pre-ovulatory) contains a single primary oocyte arrested at the end of prophase I. Oocyte growth occurs from the primary to the pre-antral follicle stages in a 3-weeks period. Oocyte maturation leads to the resumption of meiosis and ovulation of a secondary oocyte arrested in metaphase II. Meiosis II is completed upon fertilization. Zygotic genome activation (ZGA) is initiated in late 1-cell embryo and complete in 2-cell embryo stages. The indicative timing of folliculogenesis is indicated below [15]. dpp, days post partum. (B) Dynamic expression of TBP (blue) and TBPL2 (pink) proteins. While both TBP and TBPL2 proteins are present in primordial follicle oocytes, TBP is not present during oocyte growth, being replaced by TBPL2. After oocyte growth, TBPL2 protein is not detected anymore. Only TBP protein reappears after fertilization. (C) Evolution of the maternal transcriptome (beige). Oocyte growth is characterized by an important increase in RNA polymerase II transcription activity (red curve) driven by the TBPL2 machinery. Transcription ceases after oocyte growth and remains silent until ZGA. A major reshaping of the maternal transcriptome begins with oocyte maturation by maternally controlled mRNA decay (green curve) degrading 50% of the transcripts, while only 30% remain at fertilization. The degradation is reinforced after ZGA by embryonically controlled mRNA decay products (blue curve).

Figure 2.. Dynamics of maternal transcriptome translation and degradation during oocyte growth and MZT.

(A) During oocyte growth, dormant mRNAs have cytoplasmic polyadenylation elements (CPE) close to their poly(A) signal (PAS) in their 3′ UTR and have a short poly(A). They are associated with RNA binding proteins CPEB1, ZAR1/2 and MSY2 in the cytoplasmic lattices (CPL) and are not translated. The degradation of mRNA during this period is not well characterized, but terminal 3′ uridylation by TUT4 or TUT7 has been shown to be involved. (B) Upon initiation of oocyte maturation, phosphorylation of MSY2 and CPEB1 leads to the readenylation of the dormant mRNAs and activation of their translation. The combination of the CPE and PAS elements contribute to different regulation of translatability. Translation of proteins coding for the MZT licensing factor BTG4, or subunits of the decapping (DCP) and CCR4-NOT complexes is induced during this period. In parallel, the transcripts that were translated during oocyte growth are degraded. At least three pathways of CCR4-NOT recruitment have been described: (i) the MZT licensing factor BTG4 which interacts with the poly(A) binding proteins (PABP), PABPC1L and PABPN1L and with the CNOT7 or CNOT8 deadenylase subunits of the CCR4-NOT complex, (ii) the AU-rich element (ARE) binding protein ZFP36L2, which recruits CCR4-NOT via its CNOT6L deadenylase subunit, and (iii) the m6A reader YTFHDF2. Activity of the DCP complex is associated with the degradation of maternal mRNAs during this period. The implication XRN1 exoribonuclease has not been studied, however, activity of EXOSC10 exoribonuclease of the exosome complex is important during this phase. (C) Zygotic gene expression of TUT4 and TUT7 is reinforcing the action of the maternal decay proteins, such as BTG4 and CCR4-NOT, and accelerating the degradation of maternal mRNA with longer 3′ UTR that resisted to the maternally controlled decay. Question marks indicate that the implication of these proteins have not yet been studied.

Figure 3.. The maternal transcriptome degradation is regulated by decay pathways controlled by two transcriptional initiation machineries.

Two initiation machinery switches occur in the life time of the maternal transcriptome: at the beginning of oocyte growth and at the zygotic genome activation (ZGA) after fertilization. The bulk of the maternal transcriptome is produced by transcription initiated by the TBPL2/TFIIA complex (blue) that interacts preferentially with TATA boxes (TATA) of core promoters with sharp promoter architecture. Active RNA decay during this phase has been recently suggested [26], probably controlled by TBPL2/TFIIA initiated transcripts (blue line). After growth, transcription is silent and the different phases of maternal transcriptome degradation are under the control of proteins translated from dormant transcripts transcribed during the oocyte growth (dashed blue line). After ZGA, the degradation of the maternal transcriptome is reinforced by zygotically expressed proteins (orange line), leading to the disappearance of the maternal transcriptome after the four-cell stage. An interesting hypothesis is that a similar complete degradation of the initial transcriptome inherited from the TFIID/TBP transcription initiation occurs during oocyte growth (question mark). Note that there is an available resource on transcripts dynamics during maternal to zygotic transition [93].