Elevated RIF1 Participates in the Epigenetic Abnormalities of Zygotes by Regulating Histone Modifications on MuERV-L in Obese Mice

Abstract Background Maternal obesity impairs embryonic developmental potential and has significantly increases metabolic risks in offspring. However, the epigenetic transmission mechanism of maternal metabolic abnormalities is still poorly understood. Methods We induced an obesity model in female mice by high-fat diet (HFD) feeding. The effects of a HFD on the developmental potential of oocytes and embryos, metabolic phenotype, and epigenetic modifications were investigated. The efficacy of metformin administration was assessed. Finally, the regulatory pathway of epigenetic remodeling during zygotic genome activation (ZGA) was explored. Results Maternal HFD significantly impaired glucose tolerance in F0 mice, and increased the risk of metabolic disorders in F1 mice. Maternal HFD also decreased embryonic developmental potential, increased ROS and γH2AX, and reduced the mitochondrial membrane potential (MMP) within oocytes, causing high levels of oxidative stress damage and DNA damage. Starting with this clue, we observed significantly increased RIF1 and shortened telomeres in obese mice. Significant abnormal DNA methylation and histone modification remodeling were observed during ZGA in obese mice, which may be coregulated by RIF1 and the ZGA marker gene MuERV-L. Metformin treatment reduced RIF1, and partially improved ZGA activation status by rescuing epigenetic modification remodeling in oocytes and preimplantation embryos of obese mice. RIF1 knockdown experiments by Trim-Away methods showed that RIF1 degradation altered the H3K4me3 and H3K9me3 enrichment and then triggered the MuERV-L transcriptional activation. Moreover, the ChIP-seq data analysis of RIF1 knockout also showed that RIF1 mediates the transcriptional regulation of MuERV-L by changing the enrichment of H3K4me3 and H3K9me3 rather than DNA methylation. Conclusion Elevated RIF1 in oocytes caused by maternal obesity may mediate abnormal embryonic epigenetic remodeling and elevated metabolic risk in offspring by regulating histone modifications on MuERV-L. Metformin treatment can partially rescue the abnormal epigenetic remodeling and prevent epigenetic transmission of maternal metabolic abnormalities.