Discordant effects of maternal age on the human MII oocyte transcriptome.

Abstract

While advanced maternal age is associated with significant changes in oocyte gene expression, these are not global changes but limited to a fraction of the transcriptome. However, there is little consensus on the specific genes affected, and on the transcriptomic signatures of age-related declines in oocyte quality. To characterize the effects of age on the human MII oocyte transcriptome, here we take a two-part approach. We first generated single-oocyte Smart-seq2 datasets from 10 younger (21-29 years) and 10 older (37-43 years) donors, identifying genes differentially expressed between the two groups, then cross-referenced our results with those of 12 studies (9 human, 3 mouse) performing equivalent analyses using a variety of single-cell transcriptomic or microarray platforms. Technical differences notwithstanding, we found considerable discordance between the datasets, suggesting that age-related signatures of differential gene expression are not easily reproducible. Independent corroboration of age-associated changes in expression was limited to few genes, with the vast majority only supported by one of the 13 datasets, including our own. Nevertheless, we identified 40 genes whose expression significantly altered with age in multiple studies, highlighting common processes underlying ageing, including dysregulated proteostasis. As human Smart-seq2 oocyte libraries are challenging to procure and rare in public archives, we next implemented a meta-analytic method for their re-use, combining our 20 oocytes with 130 pre-existing libraries sourced from 12 different studies and representing a continuous age range of 18-43 years. We identified 25 genes whose expression level significantly correlated with age and corroborated 14 of these genes with RT-PCR, including the proteasomal subunits PSMA1 and PSMA2, both of which were downregulated in older oocytes. Overall, our findings are consistent with both pronounced inter-oocyte heterogeneity in transcription and with oocyte ageing being a multifactorial process to which bona fide transcriptomic changes may only play a restricted role, while proteomic changes play more pronounced roles.