MiR-425-5p suppression of Crebzf regulates oocyte aging via chromatin modification

Abstract

AbstractFemale infertility due to declining oocyte quality with age remains a significant challenge for patients and physicians, despite extensive research efforts. Recent studies suggest that microRNAs (miRNAs), which respond to various stressors in the aging process, may provide a promising solution. With the approval of small RNA drugs for clinical use, miRNA-based treatment of oocyte aging appears to be a viable option. Through high-throughput sequencing,miR-425-5pwas identified as the only miRNA elevated under natural aging and oxidative stress. Microinjection of inhibitors to inhibitmiR-425-5peffectively improved compromised phenotypes of old oocytes in vitro. Further investigation revealed thatCrebzfacts as a mediator ofmiR-425-5p's age-related functions in old oocytes. In vivo treatment withmiR-425-5pantagomirs significantly improved impaired oocyte development in reproductively old females by targetingCrebzf. Single-cell RNA sequencing revealed thatCrebzfplays a vital role in regulating mRNAs targeting histone H3, trimethylated lysine 4 (H3K4me3), a crucial marker for transcriptional silencing. Overexpression ofmiR-425-5pcould hinder oocyte maturation by downregulatingCrebzfexpression and disrupting transcriptional regulation. Our findings provide new insights into the potential ofmiR-425-5pantagomirs as a treatment for female infertility and highlight an elegant mechanism by whichmiR-425-5pinhibition ofCrebzfinhibits a developmental switch in GV oocytes by regulating a group of histone methyltransferase mRNAs.