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

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $38,382

## Abstract

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.

## Key facts

- **NIH application ID:** 10014626
- **Project number:** 5F30HD100126-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Katherine Lee
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,382
- **Award type:** 5
- **Project period:** 2019-08-02 → 2023-08-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10014626

## Citation

> US National Institutes of Health, RePORTER application 10014626, Mechanisms Linking Global Transcriptional Silencing and Zygotic Gene Activation During the Oocyte-to-Embryo Transition in Mammals (5F30HD100126-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10014626. Licensed CC0.

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