Loss of heterochromatin and retrotransposon silencing constitute an early phase in oocyte aging

Abstract

Mammalian oocyte quality reduces with female age. A well-studied aspect of this deterioration is an age-associated rise in oocyte aneuploidy. We show that prior to the occurrence of significant aneuploidy (at the age of 9 months in mouse females), epigenetic changes occur and impact oocyte quality and maturation ability. At this age- we observe a reduction in heterochromatin marks in mouse oocytes. This decrease is apparent in both constitutive heterochromatin and facultative heterochromatin marks but is absent in active euchromatic marks which remain constant. A decrease of heterochromatin marks with age is also observed in human GV oocytes from IVF treatments. Heterochromatin loss with age is associated with an elevation in retrotransposon RNA transcription and processing, an elevation in retrotransposon protein expression, elevation in DNA repair proteins nuclear localization and oocyte maturation defects. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and processing and oocyte maturation defects. Collectively, our work demonstrates an early stage of oocyte aging, characterized by the loss of heterochromatin associated chromatin marks and activation of retrotransposons which cause DNA damage and impair oocyte maturation. We hypothesize that this heterochromatin loss serves as an oocyte associated "epigenetic clock" and is exploited by the cell as an oocyte QC mechanism. One Sentence SummaryOocyte aging includes an early pre-aneuploidy phase when loss of repressive chromatin marks occurs as well as retrotransposon activation and egg maturation defects.