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

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. This study reports single‐oocyte transcriptome analysis with RamDA‐seq during aging and calorie restriction in mice. Oocytes undergo aging‐associated transcriptome changes at a late reproductive stage, when chromosome segregation errors are pronouncedly increased, while their surrounding cumulus cells exhibit gradual transcriptome changes even at earlier life stages. Calorie restriction promotes a transcriptome shift in oocytes, accompanied with improved maintenance of chromosomal cohesin.