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MBD-seq in ovarian tissues of prenatally androgenized (PNA) mice

ABSTRACT: To investigate the molecular mechanism of PCOS underlying the hyperandrogenic phenotype, prenatally androgenized (PNA) mice were used to mimic this phenotype in women with PCOS. Methylated DNA binding domain sequencing (MBD-seq) and RNA-seq were performed on PNA mice (n=6) and control group (n=4) and validations were applied on ovarian samples from PNA mice (n=6) and control group (n=6) using MSP (methylation-specific PCR) and qPCR. The immunohistochemistry (IHC) and transmission electron microscope (TEM) profiling was separately conducted on tissue sections and granular cells of PNA mice (n=6) and control group (n=6). We identified 857 genes with differently methylated promoters and 3317 differently expressed genes in PNA mice and control group. We found that PCOS group had a down-regulation of Dnmt1 gene expression, accompanied by global hypomethylation compared with the control group. The promoter regions of Map3k1(mitogen-activated protein kinase kinase kinase 1) and Map1lc3ka (microtubule-associated protein1 light chain 3) were hypomethylated, accompanied by up-regulation of their mRNA expression, which may be involved in the regulation of PCOS through MAPK/p53 pathway activition and autophagy alteration.

ORGANISM(S): Mus musculus

PROVIDER: GSE156960 | GEO | 2020/08/28

REPOSITORIES: GEO

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Project description:BACKGROUND: Polycystic ovarian syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenism, ovarian dysfunction and polycystic ovarian morphology. Gut microbiota dysbiosis and metabolite are associated with PCOS clinical parameters. Yulin Tong Bu formula (YLTB), a traditional Chinese medicine formula, has been recently indicated to be capable of ameliorating polycystic ovary symptoms and correcting abnormal glucose metabolism. However, the therapeutic mechanism of YLTB on PCOS has not been fully elucidated.METHODS: A pseudo sterile mouse model was established during this 4-day acclimatization phase by giving the animals an antibiotic cocktail to remove the gut microbiota. Here, the therapeutic effects of YLTB on PCOS were investigated using dehydroepiandrosterone plus high-fat diet induced PCOS mice model. Female prepuberal mice were randomly divided into 3 groups; namely, the control group, PCOS group and YLTB (38.68 g/kg/day) group. To test whether this effect is associated with the gut microbiota, we performed 16S rRNA sequencing studies to analyze the fecal microbiota of mice. The relationships among metabolites, gut microbiota and PCOS phenotypes were further explored by using Spearman correlation analysis. Then, the effect of metabolite ferulic acid was then validated in PCOS mice.RESULTS: Our results showed that YLTB treatment ameliorated PCOS features (ovarian dysfunction, delayed glucose clearance, decreased insulin sensitivity, deregulation of glucolipid metabolism and hormones, etc) and significantly attenuated PCOS gut microbiota dysbiosis. Spearman correlation analysis showed that metabolites such as ferulic acid and folic acid are negatively correlated with PCOS clinical parameters. The effect of ferulic acid was similar to that of YLTB. In addition, the bacterial species such as Bacteroides dorei and Bacteroides fragilis were found to be positively related to PCOS clinical parameters, using the association study analysis.CONCLUSION: These results suggest that YLTB treatment systematically regulates the interaction between the gut microbiota and the associated metabolites to ameliorate PCOS, providing a solid theoretical basis for further validation of YLTB effect on human PCOS trials.

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MBD-seq in ovarian tissues of prenatally androgenized (PNA) mice

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