# The effect of age on epigenetic reprogramming in C.elegans

> **NIH NIH F32** · EMORY UNIVERSITY · 2020 · $65,310

## Abstract

PROJECT SUMMARY/ABSTRACT
Cellular fate is specified by differential gene expression, which is regulated by chromatin modifications allowing
for controlled access to DNA. Gametes are highly differentiated cells, harboring distinctive landscapes. They
require an epigenetic reprogramming event after fertilization to erase gamete fate and allow a totipotent zygote
to develop. Dysregulation of this process leads to developmental problems and potentially human disease. In
1972 Beguet observed that parental age affects fertility of the following generation in wild type worms (C.
elegans). Offspring from the older hermaphrodites had a smaller brood size compared to their siblings from
younger parents. To determine if this effect of age on the fertility of progeny is due to defects in maternal
epigenetic reprogramming, I performed analogous experiments in spr-5 mutant worms. SPR-5 (LSD1/KDM1A)
is a histone demethylase that removes the methylation on histone 3 lysine 4 (H3K4me2) from actively
transcribed genes. Our lab has previously shown that spr-5 mutant C. elegans have a transgenerational
sterility phenotype, due to increasing H3K4me2. Remarkably, I found that progeny of spr-5 mutant worms have
a further compromised fertility with advanced maternal age (AMA) compared to wild type. In addition, I found
that progeny of spr-5 mutant worms from early maternal age (EMA) also have reduced fertility. My results,
coupled with Beguet’s original findings, suggest that the effect of paternal age on reduced fecundity in the
offspring may be through compromised H3K4me2 reprogramming at fertilization. I propose to investigate this
possibility in my new C. elegans model through the following aims: Aim 1) determining why the spr-5 mutant
line has an exacerbated decline in the fertility of progeny from EMA and AMA hermaphrodites, Aim 2)
determining whether this decline is due to trans-generationally increased H3K4me2, and Aim 3) investigating
whether maternal age affects H3K4me2 reprogramming using ChIP-seq. Understanding the potential link
between maternal age and maternal epigenetic reprogramming is important because a) the effect of age of
fecundity that I observe is reminiscent of the maternal age effect on the rate of autism, b) the fact that mice
mutant for the SPR-5 homolog, LSD1, manifest autism-like behavior, and c) patients with LSD1 mutations
display autistic-like symptoms. Thus, these experiments are anticipated to provide a foundation for potential
translational applications in the future.

## Key facts

- **NIH application ID:** 9931048
- **Project number:** 5F32HD097920-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Onur Birol
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931048

## Citation

> US National Institutes of Health, RePORTER application 9931048, The effect of age on epigenetic reprogramming in C.elegans (5F32HD097920-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9931048. Licensed CC0.

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