Wasserzug-Pash, P. | Search bioRxiv

bioRxiv2024

Dosage compensation of transposable elements in mammals

In mammals, X-linked dosage compensation involves two processes: X-chromosome inactivation (XCI) to balance X chromosome dosage between males and females, and hyperactivation of the remaining X chromosome (Xa-hyperactivation) to achieve X-autosome balance in both sexes. Studies of both processes have largely focused on coding genes and have not accounted for transposable elements (TEs) which comprise 50% of the X-chromosome, despite TEs being suspected to have numerous epigenetic functions. This oversight is due in part to the technical challenge of capturing repeat RNAs, bioinformatically aligning them, and determining allelic origin. To overcome these challenges, here we develop a new bioinformatic pipeline tailored to repetitive elements with capability for allelic discrimination. We then apply the pipeline to our recent So-Smart-Seq analysis of single embryos to comprehensively interrogate whether X-linked TEs are subject to either XCI or Xa-hyperactivation. With regards to XCI, we observe significant differences in TE silencing in parentally driven "imprinted" XCI versus zygotically driven "random" XCI. Chromosomal positioning and genetic background impact TE silencing. We also find that SINEs may influence 3D organization during XCI. In contrast, TEs do not undergo Xa-hyperactivation. Thus, while coding genes are subject to both forms of dosage compensation, TEs participate only in Xi silencing. Evolutionary and functional implications are discussed.

genetics↗

bioRxiv2020

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

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.

cell biology↗