Single-cell RNA sequencing of Zfp36l2 knock-out and floxed GV mouse oocytes.. Mus musculus

Global transcriptional silencing is a highly conserved evolutionary event central to the transition from the fully differentiated oocyte to the totipotent embryo. Despite its importance in the development of all animals, this pivotal genome-wide event remains poorly understood. Here, we report the unexpected finding that oocyte global transcriptional silencing depends on an mRNA decay activator. Oocyte-specific loss of ZFP36L2—an RNA-binding protein critical for AU-rich element-mediated mRNA decay—prevents oocytes from undergoing global transcriptional silencing. ZFP36L2- deficient oocytes are developmentally incompetent, with defects in maturation and fertilization leading to complete female infertility. Single cell RNA-seq analysis revealed that ZFP36L2 regulates scores of transcription regulators with central roles in chromatin modification and transcription initiation and elongation. This dysregulation resulted in failure to accumulate histone methylation marks associated with the silent, competent state. Our results define a critical role for an oocyte mRNA decay activator in the downregulation of transcription activators, leading to histone methylation, global transcriptional silencing and competence to transition from oocyte to embryo. Overall design: Examination of differential gene expression in mouse oocytes upon loss of Zfp36l2.