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Maternal obesity disrupts histone modifications mediated by Ezh2 and Ampk interactions and induces cell fate defects during embryonic cortical neurogenesis. [ChIP-Seq]

ABSTRACT: In this study, we have used a rat model of maternal obesity induced by high fat diet (HFD) prior to and during gestation to investigate the cellular and molecular repercussions of maternal obesity on embryonic cortical neurogenesis. Maternal obesity is noted to substantially disrupt neurogenesis, leading not only to imbalances in cell proliferation vs neuronal differentiation ratios but also prompting a shift towards astrogliogenesis. Differentially expressed genes (DEGs) revealed disruptions in key developmental signaling pathways and reduced Akt phosphorylation particularly notable at the E14.5. These changes were associated with epigenetic alterations, mainly the differential expression and phosphorylation of Ezh2 and subsequent changes in global histone modifications. ChIP-seq revealed reduced H3K27me3 at genes upregulated due to maternal obesity which could have resulted from reduced expression and increased phosphorylation of Ezh2 at Thr311. Interestingly Ezh2 also showed increased O-GlcNAcylation in HFD embryos along with increased association with Ampk-Thr172 in accordance with previous studies showing that Ezh2-Thr311p is catalyzed by Ampk. These results led to propose an epigenetic gene regulatory mechanism mediated by Ampk and Ezh2 interactions resulting in reduced H3K27me3 and de-repression of key developmental genes which could have led to cell fate defects observed in the developing embryo brain cortex due to maternal obesity.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE255917 | GEO | 2025/03/05

REPOSITORIES: GEO

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Project description:Maternal obesity can program metabolic syndrome in offspring but the mechanisms are not well characterized. Moreover, the consequences of maternal overnutrition in the absence of frank obesity remain poorly understood. This study aimed to determine the effects of maternal consumption of a high fat-sucrose diet on the skeletal muscle metabolic and transcriptional profiles of adult offspring. Female Sprague Dawley rats were fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. Although maternal weights were not different between groups at conception or weaning, HFD dams were ~22% heavier than chow fed dams from mid-pregnancy until 4 days post-partum. Adult male offspring of HFD dams were not heavier than controls but demonstrated features of insulin resistance including elevated plasma insulin concentration (+40%, P<0.05). Next Generation mRNA Sequencing was used to identify differentially expressed genes in the soleus muscle of offspring, and Gene Set Enrichment Analysis (GSEA) to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 pathways enriched for up-regulated genes, including cytokine signaling (P<0.005), starch and sucrose metabolism (P<0.017), and inflammatory response (P<0.024). A further 8 pathways were significantly enriched for down-regulated genes including oxidative phosphorylation (P<0.004) and electron transport (P<0.022). Western blots confirmed a ~60% reduction in the phosphorylation of the insulin signaling protein Akt (P<0.05) and ~70% reduction in mitochondrial complexes II (P<0.05) and V expression (P<0.05). On a normal diet, offspring of HFD dams developed an insulin resistant phenotype, with transcriptional evidence of muscle cytokine activation, inflammation and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of pre-pregnancy obesity can promote metabolic dysregulation and predispose offspring to type 2 diabetes. Messenger RNA profile of skeletal muscle of male offspring from female Sprague Dawley rats fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. There were 5 HFD samples compared to 6 NFD control samples.

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Maternal obesity disrupts histone modifications mediated by Ezh2 and Ampk interactions and induces cell fate defects during embryonic cortical neurogenesis. [ChIP-Seq]

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