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.
Data from humans and mice indicate that maternal age has a detrimental effect on the fitness and wellbeing of their progeny. In 1972, Beguet showed that older worms have less fertile progeny and I have demonstrated that this effect is exacerbated in mutant worms with epigenetic programming defects. The proposed studies will use our C. elegans worm model to determine how the parental age affects maternal epigenetic reprogramming.
