Chromatin Modification and Global Transcriptional Silencing in the Oocyte Mediated by the mRNA Decay Activator ZFP36L2

Publication date: 5 February 2018
Source:Developmental Cell, Volume 44, Issue 3
Author(s): Jennifer N. Dumdie, Kyucheol Cho, Madhuvanthi Ramaiah, David Skarbrevik, Sergio Mora-Castilla, Deborah J. Stumpo, Jens Lykke-Andersen, Louise C. Laurent, Perry J. Blackshear, Miles F. Wilkinson, Heidi Cook-Andersen
Global transcriptional silencing is a highly conserved mechanism central to the oocyte-to-embryo transition. We report the unexpected discovery that global transcriptional silencing in oocytes depends on an mRNA decay activator. Oocyte-specific loss of ZFP36L2 an RNA-binding protein that promotes AU-rich element-dependent mRNA decay prevents global transcriptional silencing and causes oocyte maturation and fertilization defects, as well as complete female infertility in the mouse. Single-cell RNA sequencing revealed that ZFP36L2 downregulates mRNAs encoding transcription and chromatin modification regulators, including a large group of mRNAs for histone demethylases targeting H3K4 and H3K9, which we show are bound and degraded by ZFP36L2. Oocytes lacking Zfp36l2 fail to accumulate histone methylation at H3K4 and H3K9, marks associated with the transcriptionally silent, developmentally competent oocyte state. Our results uncover a ZFP36L2-dependent mRNA decay mechanism that acts as a developmental switch during oocyte growth, triggering wide-spread shifts in chromatin modification and global transcription.

Graphical abstract

Teaser

Global transcriptional silencing is a highly conserved developmental event central to oocyte developmental competence. Dumdie et al. report that, unexpectedly, this germline-specific global event is driven by an mRNA decay activator. ZFP36L2 downregulates master transcriptional regulators, leading to the chromatin modification and transcriptional silencing events important for oocyte competence.


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