Loss of heterochromatin and retrotransposon silencing as determinants in oocyte aging

Peera Wasserzug-Pash, Rachel Rothman, Eli Reich, Lital Zecharyahu, Oshrat Schonberger, Yifat Weiss, Naama Srebnik, Yaara Cohen-Hadad, Amir Weintraub, Ido Ben-Ami, Hananel Holzer, Michael Klutstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant aneuploidy (9M in mouse), heterochromatin histone marks are lost, and oocyte maturation is impaired. This loss occurs in both constitutive and facultative heterochromatin marks but not in euchromatic active marks. We show that heterochromatin loss with age also occurs in human prophase I-arrested oocytes. Moreover, heterochromatin loss is accompanied in mouse oocytes by an increase in RNA processing and associated with an elevation in L1 and IAP retrotransposon expression and in DNA damage and DNA repair proteins nuclear localization. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and oocyte maturation defects. Inhibiting retrotransposon reverse-transcriptase through azidothymidine (AZT) treatment in older oocytes partially rescues their maturation defects and activity of the DNA repair machinery. Moreover, activating the heterochromatin machinery via treatment with the SIRT1 activating molecule SRT-1720, or overexpression of Sirt1 or Ezh2 via plasmid electroporation into older oocytes causes an upregulation in constitutive heterochromatin, downregulation of retrotransposon expression, and elevated maturation rates. Collectively, our work demonstrates a significant process in oocyte aging, characterized by the loss of heterochromatin-associated chromatin marks and activation of specific retrotransposons, which cause DNA damage and impair oocyte maturation.

Original languageAmerican English
Article numbere13568
JournalAging Cell
Volume21
Issue number3
DOIs
StatePublished - Mar 2022

Bibliographical note

Publisher Copyright:
© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

Keywords

  • epigenetic aging
  • heterochromatin
  • meiosis
  • oocytes
  • reproductive aging
  • retrotransposons

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