Dynamics and clinical relevance of maternal mRNA clearance during the oocyte-to-embryo transition in humans

Qian-Qian Sha,Ge Lin,Shuoping Zhang,Wei Zheng,Lei Guo,Yun-Wen Wu,Xiang-Hong Ou,Sen Li,Heng-Yu Fan

doi:10.1038/s41467-020-18680-6

Abstract

Maternal mRNA clearance is an essential process that occurs during maternal-to-zygotic transition (MZT). However, the dynamics, functional importance, and pathological relevance of maternal mRNA decay in human preimplantation embryos have not yet been analyzed. Here we report the zygotic genome activation (ZGA)-dependent and -independent maternal mRNA clearance processes during human MZT and demonstrate that subgroups of human maternal transcripts are sequentially removed by maternal (M)- and zygotic (Z)-decay pathways before and after ZGA. Key factors regulating M-decay and Z-decay pathways in mouse have similar expression pattern during human MZT, suggesting that YAP1-TEAD4 transcription activators, TUT4/7-mediated mRNA 3ʹ-oligouridylation, and BTG4/CCR4-NOT-induced mRNA deadenylation may also be involved in the regulation of human maternal mRNA stability. Decreased expression of these factors and abnormal accumulation of maternal transcripts are observed in the development-arrested embryos of patients who seek assisted reproduction. Defects of M-decay and Z-decay are detected with high incidence in embryos that are arrested at the zygote and 8-cell stages, respectively. In addition, M-decay is not found to be affected by maternal TUBB8 mutations, although these mutations cause meiotic cell division defects and zygotic arrest, which indicates that mRNA decay is regulated independent of meiotic spindle assembly. Considering the correlations between maternal mRNA decay defects and early developmental arrest of in vitro fertilized human embryos, M-decay and Z-decay pathway activities may contribute to the developmental potential of human preimplantation embryos.

Highlights

Maternal mRNA clearance is an essential process that occurs during maternal-to-zygotic transition (MZT)
Zygotic transcription activity is first detected at the 4-cell or 8-cell stage; maternal mRNAs in Clusters II and III were considered candidates for zygotic genome activation (ZGA)-dependent decay, or Zygote 8-cell mouse (M-decay) human (Z-decay); further, Cluster I was considered a candidate for a maternally encoded mRNA decay pathway that acts before ZGA and is defined as mouse (Z-decay) human (M-decay)
Studies in model systems has shown that both maternal and zygotic transcript degradation pathways are functional in the early mouse embryo during MZT4,5,30

Summary

Introduction

Maternal mRNA clearance is an essential process that occurs during maternal-to-zygotic transition (MZT). Key factors regulating M-decay and Z-decay pathways in mouse have similar expression pattern during human MZT, suggesting that YAP1-TEAD4 transcription activators, TUT4/7-mediated mRNA 3ʹ-oligouridylation, and BTG4/CCR4NOT-induced mRNA deadenylation may be involved in the regulation of human maternal mRNA stability Decreased expression of these factors and abnormal accumulation of maternal transcripts are observed in the development-arrested embryos of patients who seek assisted reproduction. The B-cell translocation gene-4 (BTG4), which is an oocyte-specific adapter protein of CCR4-NOT, was identified as an MZT-licensing factor in mice that mediated mRNA clearance prior to ZGA9–11 These mechanisms comprise the currently known M-decay pathway in mice. The maternal transcriptional coactivator YAP1 and its co-transcription factor TEAD4 were found to trigger the transcription of early zygotic genes, such as Tut4/7, and possibly genes encoding other unidentified mRNA destabilizers[14,15] These mechanisms comprise key components of the murine Z-decay pathway. Whether the appropriate maternal mRNA degradation contributes to the cytoplasmic maturation of human oocytes and their developmental potential after in vitro fertilization (IVF)

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