Nuclear Poly(A) Binding Protein 1 (PABPN1) Mediates Zygotic Genome Activation-dependent Maternal mRNA Clearance During Mouse Early Embryonic Development. Nuclear Poly(A) Binding Protein 1 (PABPN1) Mediates Zygotic Genome Activation-dependent Maternal mRNA Clearance During Mouse Early Embryonic Development

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 first is a maternally encoded mRNA decay pathway (M-decay), while the second is zygotic genome activation (ZGA)-dependent pathway (Z-decay). However, the zygotic factors triggering maternal mRNA decay in early mammalian embryos remain largely unknown. In this study, we identify the zygotically encoded nuclear poly(A) binding protein 1 (PABPN1) as a factor required for maternal mRNA turnover, with an unpredictable cytoplasmic function. Cytoplasmic PABPN1 docks on 3ʹ-uridylated transcripts, downstream of terminal uridylyl transferases TUT4 and TUT7, and recruits 3ʹ-5ʹ exoribonuclease DIS3L2 to its targets, facilitating the decay of maternal mRNA. Pabpn1-knockout in mice resulted in preimplantation-stage mortality, due to early developmental arrest at the morula stage. This study characterizes the presence of a zygotic destabilizer of maternal mRNA and helps in elucidating the Z-decay process mechanisms, which potentially contribute to human fertility. Overall design: Zygotes, 2-cell, and 8-cell embryos of WT and Pabpn1 knockdown for replicates are performed RNA sequencing. 2-cell embryos of control and Dis3l2 knockdown for replicates are performed RNA sequencing.

胚胎的生命起始于母源mRNA清除过程，这对于胚胎发育至关重要。母源转录本的消除经由两条通路协同完成：其一为母源编码的mRNA降解通路（M-decay），其二则为依赖合子基因组激活（ZGA）的降解通路（Z-decay）。然而，目前学界对哺乳动物早期胚胎中触发母源mRNA降解的合子因子仍知之甚少。本研究鉴定出合子编码的核多聚腺苷酸结合蛋白1（PABPN1）是母源mRNA周转所需的功能因子，且其具备此前未被报道的细胞质功能。细胞质中的PABPN1可结合于末端尿苷酰转移酶TUT4、TUT7下游的3'端尿苷酸化转录本，并招募3'-5'外核糖核酸酶DIS3L2至其靶标转录本，从而促进母源mRNA的降解。小鼠体内Pabpn1基因敲除会导致植入前胚胎致死，其原因是胚胎在桑葚胚阶段出现早期发育停滞。本研究阐明了一类合子编码的母源mRNA去稳定因子，有助于解析Z-decay通路的作用机制，或可为人类生育相关研究提供潜在参考。整体实验设计：对野生型（WT）与Pabpn1基因敲低的受精卵、2-细胞期及8-细胞期胚胎进行重复RNA测序；同时对对照组与Dis3l2基因敲低的2-细胞期胚胎进行重复RNA测序。