Single‐oocyte transcriptome analysis reveals aging‐associated effects influenced by life stage and calorie restriction

Abstract

Chromosome segregation errors in oocytes lead to the production of aneuploid eggs, which are the leading cause of pregnancy loss and of several congenital diseases such as Down syndrome. The frequency of chromosome segregation errors in oocytes increases with maternal age, especially at a late stage of reproductive life. How aging at various life stages affects oocytes differently remains poorly understood. In this study, we describe aging‐associated changes in the transcriptome profile of mouse oocytes throughout reproductive life. Our single‐oocyte comprehensive RNA sequencing using RamDA‐seq revealed that oocytes undergo transcriptome changes at a late reproductive stage, whereas their surrounding cumulus cells exhibit transcriptome changes at an earlier stage. Calorie restriction, a paradigm that reportedly prevents aging‐associated egg aneuploidy, promotes a transcriptome shift in oocytes with the up‐regulation of genes involved in chromosome segregation. This shift is accompanied by the improved maintenance of chromosomal cohesin, the loss of which is a hallmark of oocyte aging and causes chromosome segregation errors. These findings have implications for understanding how oocytes undergo aging‐associated functional decline throughout their reproductive life in a context‐dependent manner.

Cumulus Cells Accelerate Postovulatory Oocyte Aging through IL1–IL1R1 Interaction in Mice

“…The development of omics provides a basis for an in-depth understanding of molecular changes in cells [ 44 ]. Transcriptome analysis of cumulus cells and oocytes revealed molecular pathways involved in reproductive aging physiology [ 45 ], such as cases where the combined analysis of cumulus cells and oocyte transcriptome sequencing revealed age-related effects influenced by life stage and calorie restriction [ 46 ]. Our study used Smart-seq 2 and RNA-seq for transcriptome sequencing in oocytes and cumulus cells, respectively.…”

“…Our study used Smart-seq 2 and RNA-seq for transcriptome sequencing in oocytes and cumulus cells, respectively. According to the relevant reports of Mishina’s use of hub genes [ 46 ], we found the top ten GSEA pathways and top ten hub genes of oocytes and cumulus cells. A combined analysis of the omics data showed that the cytokine–cytokine receptor interaction in the top ten GSEA pathways displayed abnormalities in both aging cells.…”

CHD7 in oocytes is essential for female fertility

“…In contrast, the contemporary surrounding GCs had much lower CHD7 expression levels. In another single-cell RNAseq analysis evaluating the expression levels of Chd7 in mouse oocytes and the surrounding cumulus at different ages, we obtained data showing high Chd7 expression levels in mouse GV oocytes at 2, 9, and 14 months old from GSE159281 (Figure 1B) (25).…”

The landscape of aging

“…Melatonin, a strong antioxidant, can increase telomere length and reduce inflammation during ovarian aging (Secomandi et al, 2022). Calorie restriction can also prevent aging-associated oocyte aneuploidy (Mishina et al, 2021). In addition, developments in mitochondrial replacement therapy, nuclear genome transfer, and autonomous germline mitochondrial energy transfer (AUGMENT) techniques improve oocyte quality (Reddy et al, 2015;Woods and Tilly, 2015), however clinical safety considerations require further evaluation (Tvrdá et al, 2021).…”