# Mechanisms driving the transition from oocyte to embryo:  The role of the mRNA decay activator ZFP36L2.

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $5,120

## Abstract

Project Summary
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. We have recently discovered that oocyte global
transcriptional silencing depends on an mRNA decay activator. Oocyte-specific loss of ZFP36L2—an RNA-
binding protein with a well-established role in 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. These findings strongly point to
a model in which global transcriptional silencing in the oocyte is mediated by mRNA decay. The goals of this
proposal are to both uncover the mechanism(s) by which mRNA decay by ZFP36L2 brings about global
transcriptional silencing in the oocyte and to take advantage of the insights provided by this unique genetic
model system to investigate the role of ZFP36L2-dependent chromatin modifications critical for global
transcriptional silencing and the successful transition from oocyte to embryo. To determine the role of mRNA
decay in bringing about global transcriptional silencing, we will identify the direct targets of ZFP36L2 in the
oocyte genome-wide and test the role of these factors in mediating global transcriptional silencing and oocyte
developmental competence. We will determine the role of ZFP36L2 in chromatin modification, including
histone H3 and DNA methylation, and test the role of these modifications in global transcriptional silencing in
the oocyte. Finally, we will test whether ZFP36L2-dependent chromatin modifications established in the oocyte
act to maintain global transcriptional silencing over the oocyte-to-embryo transition and/or set the stage for
activation of new transcription in the newly formed embryo.

## Key facts

- **NIH application ID:** 10388655
- **Project number:** 3R01GM124519-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Heidi Cook-Andersen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $5,120
- **Award type:** 3
- **Project period:** 2018-07-18 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388655

## Citation

> US National Institutes of Health, RePORTER application 10388655, Mechanisms driving the transition from oocyte to embryo:  The role of the mRNA decay activator ZFP36L2. (3R01GM124519-03S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10388655. Licensed CC0.

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