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.

Constitutive Heterochromatin in Eukaryotic Genomes: A Mine of Transposable Elements

“…An additional role of TEs in the heterochromatin appears to be related to the embryo development. In a recent study, the upstream region of retrotransposons belonging to few active families was identified as the nucleation sites of heterochromatin formation during early stages of embryo development in the fly [ 142 , 143 ], and similar observations have been made in mammals [ 144 ].…”

Age-Dependent in vitro Maturation Efficacy of Human Oocytes – Is There an Optimal Age?

“…These findings imply that ovarian aging as expressed by the ability to mature unstimulated oocytes starts earlier than we know from our clinical results in the IVF settings, whereas pregnancies and live birth rates tend to dramatically drop along the fifth decade of life (Broekmans et al, 2007). These maturation defects can stem from many different biological pathways and processes, which may include: a change in maturation-related ovarian processes that are altered with age (Mara et al, 2020); changes in the composition and behavior of the ovarian tissue with age (Amargant et al, 2020); epigenetic changes that occur in oocytes with age (Wasserzug-Pash and Klutstein, 2019;Wasserzug-Pash et al, 2020) and enhanced ROS (Di Emidio et al, 2014;Babayev et al, 2016) and DNA damage (Marangos et al, 2015;Wasserzug-Pash and Klutstein, 2019) in older oocytes. The results shown here emphasize that aged oocytes begin to deteriorate even before the onset of significant aneuploidy, as demonstrated in mouse oocytes (Merriman et al, 2012).…”