Abstract
A cultural trend in developed countries is favoring a delay in maternal age at first childbirth. In mammals fertility and chronological age show an inverse correlation. Oocyte quality is a contributing factor to this multifactorial phenomenon that may be influenced by age-related changes in the oocyte epigenome. Based on previous reports, we hypothesized that advanced maternal age would lead to alterations in the oocyte’s epigenome. We tested our hypothesis by determining protein levels of various epigenetic modifications and modifiers in fully-grown (≥70 µm), germinal vesicle (GV) stage oocytes of young (10-13 weeks) and aged (69-70 weeks) mice. Our results demonstrate a significant increase in protein amounts of the maintenance DNA methyltransferase DNMT1 (P = 0.003) and a trend toward increased global DNA methylation (P = 0.09) with advanced age. MeCP2, a methyl DNA binding domain protein, recognizes methylated DNA and induces chromatin compaction and silencing. We hypothesized that chromatin associated MeCP2 would be increased similarly to DNA methylation in oocytes of aged female mice. However, we detected a significant decrease (P = 0.0013) in protein abundance of MeCP2 between GV stage oocytes from young and aged females. Histone posttranslational modifications can also alter chromatin conformation. Di-methylation of H3K9 (H3K9me2) is associated with permissive heterochromatin while acetylation of H4K5 (H4K5ac) is associated with euchromatin. Our results indicate a trend toward decreasing H3K9me2 (P = 0.077) with advanced female age and no significant differences in levels of H4K5ac. These data demonstrate that physiologic aging affects the mouse oocyte epigenome and provide a better understanding of the mechanisms underlying the decrease in oocyte quality and reproductive potential of aged females.
Highlights
In mammals, there is an inverse correlation between fertility and chronological age (Broekmans et al, 2009; Qiao et al, 2014)
We observed a trend towards increased levels of global DNA methylation (P = 0.09; Figure 1B) in oocytes of aged females when compared to their young counterparts
We identified a significant increase in levels of DNMT1 protein with increased maternal age (P = 0.003; Figure 1A)
Summary
There is an inverse correlation between fertility and chronological age (Broekmans et al, 2009; Qiao et al, 2014). The age-related decline in mammalian female fertility is a multifactorial phenomenon greatly influenced by oocyte quantity (Faddy, 2000) and quality (Cohen et al, 1999), as well as lowered embryo development (Talbert, 1971; van Kooij et al, 1996; Lopes et al, 2009). In human and mouse the incidence of chromosomal abnormalities increases with female age due to non-disjunctions and other related errors in meiosis (Plachot, 2001; Pan et al, 2008). Meiotic chromosomes isolated from oocytes of aged mice are more rigid than their young counterparts (Hornick et al, 2015). In mice, a useful animal model for the study of aging-related events (Danilovich and Ram Sairam, 2006; Vanhooren and Libert, 2013), increased biological age is associated with alterations of the oocyte’s transcriptome (Hamatani et al, 2004; Pan et al, 2008; Yue et al, 2012) and epigenome (Akiyama et al, 2006; Manosalva and Gonzalez, 2009; Manosalva and González, 2010)
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