# Epigenetic gene regulation in the germline

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $220,141

## Abstract

ABSTRACT
One of the greatest mysteries in biology concerns how life has perpetuated, and continues to perpetuate, from
generation to generation. A key feature of the mammalian germline is its sexual dimorphism: spermatogenesis
and oogenesis. These dimorphic developmental processes are inherently complex, and this complexity poses
significant challenges to understanding the perpetuity of life and the development of treatments for various
germline-derived genetic and epigenetic diseases. Thus, in this R35 application, our research directions
converge to address the following question: How do epigenetic mechanisms govern distinct sexually
dimorphic processes in spermatogenesis and oogenesis, culminating in the generation of functional
sperm and eggs? Since I became independent ten years ago, I and my team have worked to construct a
detailed picture of the epigenetic mechanisms that govern mammalian spermatogenesis. We have shown that
the mitosis-to-meiosis transition in germ cell development is notable for not only global changes in gene
expression but the dynamic reorganization of the epigenome; in brief, we have revealed that meiosis itself is a
process of global epigenomic reprogramming. My research program has pioneered these concepts and
developed innovative approaches to decode germline mechanisms crucial for preparing the next generation,
providing a rigorous foundation for future research.
 To understand key sexually dimorphic processes, we focus on fundamental processes in
spermatogenesis and oogenesis. In spermatogenesis, postnatal germ cells enter a stem cell stage, undergo
meiosis, and sustain long-term production of sperm. We will elucidate the global epigenetic mechanisms
underlying spermatogenesis from the stem cell stage to sperm production, with an emphasis on
dynamic changes in the epigenetic machinery and their importance to the next generation. Since, in males,
meiotic sex chromosome inactivation (MSCI) functions as a key sexually dimorphic process, we will also
determine the molecular functions of DNA damage response pathways—which direct MSCI—in the
epigenetic regulation of the sex chromosomes. In contrast, female germ cells undergo meiosis in embryos
and enter a prolonged stage of meiotic arrest—spanning decades in humans—prior to oocyte maturation. We
will determine epigenetic mechanisms underlying critical stages of oogenesis to complement our study
of male germ cells. Ultimately, we will reveal distinct features and unifying principles of spermatogenesis
and oogenesis. Taking all of this together, we are uniquely positioned to clarify how fundamental germline
mechanisms intersect to ensure genome maintenance, genome defense, and epigenetic gene regulation on a
systemic level. The research directions proposed in this application are cohesive and synergistic, with high
potential to sustain research progress and inform significant, transformative advances in germline biology,
human reproduction, and reproductive health in gene...

## Key facts

- **NIH application ID:** 10581898
- **Project number:** 3R35GM141085-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Satoshi Namekawa
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $220,141
- **Award type:** 3
- **Project period:** 2021-07-05 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10581898

## Citation

> US National Institutes of Health, RePORTER application 10581898, Epigenetic gene regulation in the germline (3R35GM141085-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10581898. Licensed CC0.

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