Nuclear poly(A) binding protein 1 (PABPN1) mediates zygotic genome activation-dependent maternal mRNA clearance during mouse early embryonic development

Abstract

An embryo starts its life with maternal mRNA clearance, which is crucial for embryonic development. The elimination of maternal transcripts occurs by the joint action of two pathways: the maternally encoded mRNA decay pathway (M-decay) and the zygotic genome activation (ZGA)-dependent pathway (Z-decay). However, zygotic factors triggering maternal mRNA decay in early mammalian embryos remain largely unknown. In this study, we identified the zygotically encoded nuclear poly(A) binding protein 1 (PABPN1) as a factor required for maternal mRNA turnover, with a previously undescribed cytoplasmic function. Cytoplasmic PABPN1 docks on 3′-uridylated transcripts, downstream of terminal uridylyl transferases TUT4 and TUT7, and recruits 3′-5′ exoribonuclease DIS3L2 to its targets, facilitating maternal mRNA decay. Pabpn1-knockout in mice resulted in preimplantation stage mortality due to early developmental arrest at the morula stage. Maternal mRNAs to be eliminated via the Z-decay pathway failed to be removed from Pabpn1-depleted embryos. Furthermore, PABPN1-mediated Z-decay is essential for major ZGA and regulates the expression of cell fate-determining factors in mouse preimplantation embryos. This study revealed an unforeseen cytoplasmic function of PABPN1 coupled with early embryonic development, characterized the presence of a zygotic destabilizer of maternal mRNA, and elucidated the Z-decay process mechanisms, which potentially contribute to human fertility.

scm6A-seq reveals single-cell landscapes of the dynamic m6A during oocyte maturation and early embryonic development

“…ZGA of the mice zygote embryos begins at the late 1-cell embryos, and many studies have pointed to the significance of chromatin remodeling in zygotic transcription initiation, including DNA methylation, histone modifications, chromatin accessibility, high-order chromatin structures formation, and RNA polymerase II (Pol II) binding [19][20][21][22] . Interestingly, in addition to the newly synthesized zygotic transcripts, ZGA-dependent maternal RNA clearance processes are crucial for early embryonic development 23,24 . Moreover, RNA metabolism during ZGA results in the heterogeneity of epigenomic modification among blastomeres and suggests transcriptome-wide regulation initiated at the 2-cell embryonic stage 25,26 .…”

Spatiotemporal regulation of maternal mRNAs during vertebrate oocyte meiotic maturation

“…One such example is PABPN1. Zhao et al (2022) demonstrated that cytoplasmic PABPN1 is an early expressed zygotic factor and that it docks on uridylated transcripts and recruits 3 0 -5 0 exoribonuclease DIS3L2 to its targets, facilitating maternal mRNA decay (Zhao et al, 2022). Pabpn1 mRNA levels were significantly increased after fertilization and remained at a relatively high level until the eight-cell stage.…”

“…All these factors are deposited in oocytes and are responsible for stage‐specific degradation of maternal mRNAs during M‐decay. Maternally expressed BTG4 and the CCR4‐NOT deadenylase complex continue to serve for Z‐decay, but likely require reinforcement from zygotic factors for timely removal of maternal mRNAs (Sha et al ., 2020 b ; Zhao et al ., 2022).…”

“…In addition, timely elimination of maternal mRNAs is also crucial for proper oocyte‐to‐zygote transition. Increasing evidence indicates that multiple mechanisms, involving RBPs (Zhao et al ., 2020, 2022; Dumdie et al ., 2018; Sha et al ., 2018), posttranscriptional modifications (Chang et al ., 2018; Morgan et al ., 2017; Ivanova et al ., 2017; Zhao et al ., 2017), and small RNAs (Yang et al ., 2019; Roovers et al ., 2015; Liu et al ., 2017 a ; Stein et al ., 2015), account for maternal mRNA stabilization and destabilization during oocyte maturation. Despite these exciting findings, a comprehensive understanding of the regulation of mRNA fate during oocyte maturation is yet to be established.…”

scm6A-seq reveals single-cell landscapes of the dynamic m6A during oocyte maturation and early embryonic development

“…Mouse ZGA begins at the late 1-cell embryos, and many studies have pointed to the significance of chromatin remodeling in zygotic transcription initiation, including DNA methylation, histone modifications, chromatin accessibility, high-order chromatin structures formation, and RNA polymerase II (Pol II) binding [14][15][16][17] . Interestingly, in addition to the newly synthesized zygotic transcripts, ZGA-dependent maternal RNA clearance processes are crucial for early embryonic development 18,19 . Moreover, RNA metabolism during ZGA results in the heterogeneity of epigenomic modification among blastomeres and suggests transcriptome-wide regulation initiated at the 2-cell embryonic stage 20,21 .…”