Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis [scBS-seq]
Advancing maternal age causes a progressive reduction in fertility. The decline in developmental competence of the oocyte with age is likely to be a consequence of multiple contributory factors. Loss of epigenetic quality of the oocyte should be considered as one factor, as epigenetic errors could impair early developmental events or programme adverse outcomes in offspring that manifest only later in life. Here, we undertake joint profiling of the transcriptome and DNA methylome in individual oocytes from reproductively young and old female mice. We find reduced complexity as well as increased variance in the transcriptome in oocytes from aged females. This heterogeneity is reflected in the identification of discrete sub-populations of oocytes, including those with a transcriptome characteristic of oocytes with immature chromatin configuration, as well as those with a young-like transcriptome. Oocytes from older females had on average reduced CpG methylation, but the characteristic bimodal methylation landscape of the oocyte was preserved. Germline differentially methylated regions of imprinted genes were appropriately methylated irrespective of age. For the majority of differentially expressed transcripts, the absence of correlated methylation changes suggests a post-transcriptional basis for most age-related effects on the transcriptome. However, we did find differences in gene-body methylation at which there were corresponding changes in gene expression, indicating age-related effects on transcription that translate into methylation differences. Interestingly, oocytes varied in expression and methylation of these genes, which could contribute to variable competence of oocytes or penetrance of maternal age-related phenotypes in offspring. Overall design: Fully-grown germinal vesicle (GV) oocytes were collected from the ovaries of C57BL/6Babr virgin females aged 12 weeks (young, n=39) or 44-54 weeks (old, n=41)