# 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 · $331,713

## 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:** 10164802
- **Project number:** 5R01GM124519-04
- **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:** $331,713
- **Award type:** 5
- **Project period:** 2018-07-18 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164802

## Citation

> US National Institutes of Health, RePORTER application 10164802, Mechanisms driving the transition from oocyte to embryo:  The role of the mRNA decay activator ZFP36L2 (5R01GM124519-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10164802. Licensed CC0.

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