Abstract
In somatic cells/tissues, methylation of ribosomal DNA (rDNA) increases with age and age‐related pathologies, which has a direct impact on the regulation of nucleolar activity and cellular metabolism. Here, we used bisulfite pyrosequencing and show that methylation of the rDNA transcription unit including upstream control element (UCE), core promoter, 18S rDNA, and 28S rDNA in human sperm also significantly increases with donor's age. This positive correlation between sperm rDNA methylation and biological age is evolutionarily conserved among mammals with widely different life spans such as humans, marmoset, bovine, and mouse. Similar to the tandemly repeated rDNA, methylation of human α‐satellite and interspersed LINE1 repeats, marmoset α‐satellite, bovine alpha‐ and testis satellite I, mouse minor and major satellite, and LINE1‐T repeats increases in the aging male germline, probably related to their sperm histone packaging. Deep bisulfite sequencing of single rDNA molecules in human sperm revealed that methylation does not only depend on donor's age, but also depend on the region and sequence context (A vs. G alleles). Both average rDNA methylation of all analyzed DNA molecules and the number of fully (>50%) methylated alleles, which are thought to be epigenetically silenced, increase with donor's age. All analyzed CpGs in the sperm rDNA transcription unit show comparable age‐related methylation changes. Unlike other epigenetic aging markers, the rDNA clock appears to operate in similar ways in germline and soma in different mammalian species. We propose that sperm rDNA methylation, directly or indirectly, influences nucleolar formation and developmental potential in the early embryo.
Highlights
Older men have a much lower chance of achieving a pregnancy by natural conception and assisted reproduction as well (Dain, Auslander, & Dirnfeld, 2011)
We propose that increased ribosomal DNA (rDNA) methylation in sperm of old males decreases the developmental potential of the resulting embryos, contributing to age-related fertility problems
Paternal age is associated with increased sperm methylation of rDNA and other repetitive DNA families, which preserve nucleosomes and a more open chromatin organization in mature sperm
Summary
Older men have a much lower chance of achieving a pregnancy by natural conception and assisted reproduction as well (Dain, Auslander, & Dirnfeld, 2011). Each of the 53 analyzed CpG sites in the rDNA transcription unit displayed a highly significant positive correlation with donor's age in both sperm cohorts (Table S3). The mean sperm methylation of all four analyzed rDNA regions significantly (p < 0.0001) increased with donor's age (Figure 1).
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