Abstract
BackgroundMaternal obesity impairs embryonic developmental potential and significantly increases the risks of metabolic disorders in offspring. However, the epigenetic transmission mechanism of maternal metabolic abnormalities is still poorly understood.MethodsWe established an obesity model in female mice by high-fat diet (HFD) feeding. The effects of the HFD on the developmental potential of oocytes and embryos, the 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.ResultsMaternal HFD consumption significantly impaired glucose tolerance and increased the risk of metabolic disorders in F0 and F1 mice. Maternal HFD consumption also decreased embryonic developmental potential, increased reactive oxygen species (ROS) and γH2AX levels, 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 levels and shortened telomeres in obese mice. Moreover, 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 levels, and partially improved ZGA activation status by rescuing epigenetic modification remodeling in oocytes and preimplantation embryos of obese mice. RIF1 knockdown experiments employing Trim-Away methods showed that RIF1 degradation altered the H3K4me3 and H3K9me3 enrichment and then triggered the MuERV-L transcriptional activation. Moreover, ChIP-seq data analysis of RIF1 knockouts also showed that RIF1 mediates the transcriptional regulation of MuERV-L by changing the enrichment of H3K4me3 and H3K9me3 rather than by altered DNA methylation.ConclusionElevated RIF1 in oocytes caused by maternal obesity may mediate abnormal embryonic epigenetic remodeling and increase metabolic risk in offspring by regulating histone modifications on MuERV-L, which can be partially rescued by metformin treatment.
Highlights
Obesity has become a global epidemic and a worldwide public health concern
We found that the expression of Rap1-interacting factor 1 (RIF1) was localized to the nucleus and that the average fluorescence intensity of RIF1 was significantly stronger in high-fat diet (HFD) oocytes than in control diet (CD) oocytes
As RIF1 was related to the DNA damage response, we evaluated the intensity of γH2AX again and found that metformin partially counteracted the elevated γH2AX caused by the HFD (P < 0.01, Fig. 4D)
Summary
Obesity has become a global epidemic and a worldwide public health concern. A wide range of diseases caused by obesity seriously affect people’s health. Women of reproductive age are challenged by obesity (Ng et al 2014). Due to the pregnancy and offspring factors, more health problems and potential risks need to be considered in. The increased risks of metabolic abnormalities in offspring are probably associated with epigenetic abnormalities in maternal oocytes (Ou et al 2019). It is not understood how these epigenetic abnormalities in maternal gametes are passed on to embryos, considering the extensive erasure and reconstruction of epigenetic modifications after zygotic genome activation (ZGA) (Eckersley-Maslin et al 2018; Xia et al 2019). Maternal obesity impairs embryonic developmental potential and significantly increases the risks of metabolic disorders in offspring. The epigenetic transmission mechanism of maternal metabolic abnormalities is still poorly understood
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