Mechanisms Linking Global Transcriptional Silencing and Zygotic Gene Activation During the Oocyte-to-Embryo Transition in Mammals

点击翻译按钮获取中文摘要

Abstract Remarkably, the dynamic transition from the fully differentiated oocyte to the totipotent embryo occurs in the complete absence of de novo transcription. Transcription is globally silenced during the final stages of oocyte growth and does not significantly resume until the zygotic genome activation (ZGA) in the late 2-cell embryo stage. Although critical for development from worms to humans, how transcriptional silencing is achieved on a global scale and subsequently reactivated without new transcription across the oocyte-to- embryo transition remains poorly understood. A deeper understanding of the mechanisms underlying these developmental transitions is critical for advances in stem cell technologies and infertility therapies. We have recently discovered (Dumdie et al., Dev Cell, 2018) that oocyte global transcriptional silencing depends on the mRNA decay activator ZFP36L2—an RNA-binding protein with a well-established role in AU-rich element-mediated mRNA decay. Oocyte-specific loss of ZFP36L2 prevents oocytes from undergoing global transcriptional silencing and leads to complete female infertility. Single-cell RNA-seq revealed that ZFP36L2 downregulates mRNAs encoding factors regulating transcription and chromatin modification, including a specific group of mRNAs encoding histone lysine demethylases (KDMs) targeting histones H3K4 and H3K9. We showed that ZFP36L2 can bind and degrade these KDM mRNAs, suggesting a direct role for ZFP36L2-mediated mRNA decay in regulating histone methylation. Consistent with this, Zfp36l2 knockout resulted in the failure to accumulate H3K4 and H3K9 methylation associated with the transcriptionally silent, developmentally competent oocyte state. Together, these results define a critical role for an mRNA decay activator in oocyte developmental competence and suggest a model in which mRNA decay by ZPF36L2 serves as a developmental switch to downregulate transcriptional regulators, trigger wide-spread shifts in epigenetic marks, bring about global transcriptional silencing, and set the stage for a successful transition from oocyte to embryo. The goal of this proposal is to test each stage of this model—to dissect the specific mechanism(s) by which ZFP36L2-dependent mRNA decay contributes to chromatin modifications in the oocyte; to investigate the role of these chromatin modifications in bringing about global transcriptional silencing; and to uncover the contribution of histone methylation in the oocyte to transcription reactivation in the newly formed embryo.