The effects of biological aging on global DNA methylation, histone modification, and epigenetic modifiers in the mouse germinal vesicle stage oocyte

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.

Is Aberrant DNA Methylation a Key Factor in Molar Incisor Hypomineralization?

“…In this study, we established that among children diagnosed with MIH, who had older siblings, a higher level of global DNA methylation was observed in comparison with children who were born earlier, an outcome which might be linked with the age of the mother. Marshall et al observed a higher level of global DNA methylation in oocytes of aged female mice in comparison to young females [ 18 ]. On the other hand, Markunas et al identified a distinctive pattern of reduced DNA methylation in the blood of infants, which was correlated with the mother’s age at the time of labor [ 19 ], but they were not able to explain the mechanism through which the mother’s age impacts on the creation of permanent epigenetic alterations in offspring and suggested that these might be caused by inheritance of an altered maternal chromatin state.…”

Influence of maternal age on intracytoplasmic sperm injection outcome and global deoxyribonucleic acid methylation in women undergoing intracytoplasmic sperm injection cycle

“…These findings are matching with the study designed by Marshall and his colleagues where they found an increase in the level of global DNA methylation in aged women compared to young women. 19 It is worth mentioning that DNA methylation plays a critical role in transcriptional suppression and chromatin compaction. Therefore, the increase in the level of global DNA methylation with increased female age is a contributor to the alteration of oocyte transcription which influences the development of the embryo.…”

“…[16][17][18] A previous study found an association between the increase in DNA methylation level and advancing age. 19 Due to the lack of available information and variances in the results of studies that evaluate the relationship between the global DNA methylation, ICSI outcomes and maternal age. This study was designed in order to investigate the influence of maternal age on the ICSI outcomes which included the number of collected oocytes, mature oocytes, fertilization rate, number of embryos transferred in women undergoing to first ICSI cycle, evaluate the impact of maternal age on the global DNA methylation and study the association between maternal age and other investigated clinical parameters.…”

Epigenetic regulation in premature ovarian failure: A literature review

“…In addition, Yu et al conducted mRNA-Seq and genome-wide DNA methylation studies in human ovarian GCs and found that compared with young healthy donors, older women with a natural age-related decline in ovarian function showed lower gene expression (1,809 genes were downregulated) that was correlated with higher gene body methylation and 3′-end GC density ( Yu et al, 2015 ). According to Marshall et al, the expression level of the DNA methyltransferase Dnmt1 in oocytes increased in 69- to 70-week-old mice compared with 10- to 13-week-old mice, and the DNA and histone H3K9me2 methylation levels also increased ( Marshall et al, 2018 ). However, Yue et al found that the DNA methylation level of metaphase II (MII) oocytes in 35- to 40-week-old mice decreased compared with six- to 8 week-old mice, and the expression levels of Dnmt1, Dnmt3a, Dnmt3b, and Dnmt3L decreased ( Yue et al, 2012 ).…”