Abstract
An age-dependent increase in ribosomal DNA (rDNA) methylation has been observed across a broad spectrum of somatic tissues and the male mammalian germline. Bisulfite pyrosequencing (BPS) was used to determine the methylation levels of the rDNA core promoter and the rDNA upstream control element (UCE) along with two oppositely genomically imprinted control genes (PEG3 and GTL2) in individual human germinal vesicle (GV) oocytes from 90 consenting women undergoing fertility treatment because of male infertility. Apart from a few (4%) oocytes with single imprinting defects (in either PEG3 or GTL2), the analyzed GV oocytes displayed correct imprinting patterns. In 95 GV oocytes from 42 younger women (26-32 years), the mean methylation levels of the rDNA core promoter and UCE were 7.4±4.0% and 9.3±6.1%, respectively. In 79 GV oocytes from 48 older women (33-39 years), methylation levels increased to 9.3±5.3% (P = 0.014) and 11.6±7.4% (P = 0.039), respectively. An age-related increase in oocyte rDNA methylation was also observed in 123 mouse GV oocytes from 29 4-16-months-old animals. Similar to the continuously mitotically dividing male germline, ovarian aging is associated with a gain of rDNA methylation in meiotically arrested oocytes. Oocytes from the same woman can exhibit varying rDNA methylation levels and, by extrapolation, different epigenetic ages.
Highlights
In developed countries, the trend towards delayed parenthood has been constantly increasing
Our results suggest that human ovarian aging is associated with increasing oocyte methylation of the ribosomal DNA (rDNA) promoter and upstream control element (UCE)
The 45S pre-rRNA transcript of the rDNA transcription unit is spliced into 5.8S, 18S, and 28S rRNAs, which are assembled in the ribosomal subunits of the nucleolus
Summary
The trend towards delayed parenthood has been constantly increasing. Social, political, and cultural reasons, many parents postpone their wish for children beyond the optimal biological age [1]. This has led to an everincreasing demand for assisted reproductive technologies and prenatal diagnostic testing. It is well known that the oocyte aneuploidy rate and, the risk for fertility problems, miscarriages, and children with Down syndrome (and other chromosome disorders) increases with maternal age. Major underlying factors of reduced fertility at advanced maternal age are the decline in ovarian reserve [2] and the increased rate of chromosomal nondisjunction due to the prolonged meiotic arrest [3, 4]. Transcriptome analyses revealed numerous age-related changes in oocyte gene expression including genes for cell cycle regulation, energy production, and other critical pathways [10–13]
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