# The role of retrotransposons in female reproductive aging

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2024 · $608,274

## Abstract

Project Summary
Nearly 40% mammalian genome originates from retrotransposons. Most mammalian retrotransposons
are strictly silenced in development and physiology, yet induction of specific retrotransposons can be
observed in normal oocytes and preimplantation embryos. Interestingly, a subset of retrotransposons
confer a gene regulatory role, at least in part, by acting as alternative promoters, exons and
polyadenylation signals to regulate proximal protein-coding genes. Such retrotransposon-dependent
gene regulation frequently alter gene structure and/or gene expression, and have been shown in our
preliminary studies to play important developmental functions in oocyte biology and preimplantation
development.
Female reproductive aging presents an excellent experimental system to probe the functional importance
of retrotransposons in aging. Unlike somatic tissues which strongly repress retrotransposon expression,
oocytes and preimplantation embryos exhibit a strong induction of specific retrotransposons, possibly
due to extensive epigenetic reprogramming during these unique developmental stages. Our preliminary
studies show that aged oocytes exhibit expression alteration of specific retrotransposons, as well as
RT:gene isoforms. Interestingly, the IAPEy4 family, which is retrotransposition-competent, is strongly
induced in aged oocytes. IAPEy4 induction could lead to DNA damage and innate immune response in
aged oocytes, as a result of its retrotransposition. In addition, the MII oocyte specific MTC-Dicer1 isoform
is strongly repressed in aged oocytes. The MTC-Dicer1 encodes an N-terminally truncated Dicer isoform
that governs the transposon surveillance through post-transcriptional silencing by RNAi. These findings
suggest that altered retrotransposon expression and retrotransposon mediated gene regulation in aged
oocytes could functionally promote reproductive aging. Using genomics, mouse genetics, cell and
molecular biology, we proposed to investigate the importance of retrotransposons in female reproductive
aging. We will 1) profile retrotransposons and retrotransposon-dependent gene regulation in young and
old oocytes and somatic granulosa cells; 2) Investigate the importance of aberrant retrotransposon
induction and retrotransposition during reproductive aging; 3) investigate the importance of
retrotransposon mediated gene regulation in reproductive aging. Taken together, the proposed studies
will provide new insights into the cellular and molecular mechanisms that govern female reproductive
aging, and will add a new dimension to our understanding of retrotransposon functions in development
and disease.

## Key facts

- **NIH application ID:** 10845610
- **Project number:** 5R01AG078958-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Lin He
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $608,274
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845610

## Citation

> US National Institutes of Health, RePORTER application 10845610, The role of retrotransposons in female reproductive aging (5R01AG078958-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10845610. Licensed CC0.

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