Argonaute 2 is a key regulator of maternal mRNA degradation in mouse early embryos

Jia-Ming Zhang,Wei-Jia Wang,Yan-Shuang Mu,Kai-Lun Zheng,Chun-Ming Ding,Ming Zong,Jia-Wei Du,Jia-Qiang Wang,Wei-Bo Hou,Zhi Yin,Heng Zhang,Qing-Yuan Sun,Qing-Ran Kong,Zhong-Hua Liu

doi:10.1038/s41420-020-00368-x

Abstract

In mammalian early embryos, the transition from maternal to embryonic control of gene expression requires timely degradation of a subset of maternal mRNAs (MRD). Recently, zygotic genome activation (ZGA)-dependent MRD has been characterized in mouse 2-cell embryo. However, in early embryos, the dynamics of MRD is still poorly understood, and the maternal factor-mediated MRD before and along with ZGA has not been investigated. Argonaute 2 (Ago2) is highly expressed in mouse oocyte and early embryos. In this study, we showed that Ago2-dependent degradation involving RNA interference (RNAi) and RNA activation (RNAa) pathways contributes to the decay of over half of the maternal mRNAs in mouse early embryos. We demonstrated that AGO2 guided by endogenous small interfering RNAs (endosiRNAs), generated from double-stranded RNAs (dsRNAs) formed by maternal mRNAs with their complementary long noncoding RNAs (CMR-lncRNAs), could target maternal mRNAs and cooperate with P-bodies to promote MRD. In addition, we also showed that AGO2 may interact with small activating RNAs (saRNAs) to activate Yap1 and Tead4, triggering ZGA-dependent MRD. Thus, Ago2-dependent degradation is required for timely elimination of subgroups of maternal mRNAs and facilitates the transition between developmental states.

Highlights

Growing oocytes possess high transcriptional activity and accumulate large amounts of maternal mRNAs and proteins, which control the initial stages of development[1,2]
We suggest that the maternal mRNAs in cluster I could be degraded during the transition from MII oocyte to middle 2-cell embryo (MII/2 C degradation) before zygotic genome activation (ZGA), while the maternal mRNAs in cluster II could be degraded during the transition from middle 2-cell to early 4-cell embryos (2C/4C degradation), which may be associated with ZGA, and the degradation of the maternal mRNAs in cluster III, termed continuous degradation, might be associated with both processes
These features verified the credibility of the small activating RNAs (saRNAs) prediction, and the results suggest that AGO2 may be guided by saRNA to function on ZGA

Summary

Introduction

Growing oocytes possess high transcriptional activity and accumulate large amounts of maternal mRNAs and proteins, which control the initial stages of development[1,2]. MRD occurs during oogenesis, beyond fertilization, and is accomplished along ZGA. It acts during two sequential processes from oocyte to early embryo[8]. The maternally encoded products are exclusively used to activate the degradation pathway. In mouse embryos, the ZGA-dependent maternal mRNA clearance has been characterized at 2-cell stage, and YAP1- and TEAD4-mediated zygotic transcription is crucial for the pathway[16]. Before ZGA, embryogenesis is supported by maternal factors, which participate in the removal of maternal detritus and the robust activation of Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion