Maternal obesity alters histone modifications mediated by the interaction between EZH2 and AMPK, impairing neural differentiation in the developing embryonic brain cortex.

Neurodevelopmental disorders have complex origins that manifest early during embryonic growth and are associated with intricate gene regulation dynamics. A perturbed metabolic environment such as hyperglycemia or dyslipidemia, particularly due to maternal obesity, poses a threat to the optimal development of the embryonic central nervous system. Accumulating evidence suggests that these metabolic irregularities during pregnancy may alter neurogenesis pathways, thereby predisposing the developing fetus to neurodevelopmental disorders. One primary mechanism through which such disruptions may occur involves changes in histone modifications resulting from fluctuations in the expression of histone-modifying enzymes or the availability of their substrates. Herein, we have used a rat model of maternal obesity induced by a high-fat diet before and during gestation to investigate the cellular and molecular repercussions of maternal obesity on embryonic cortical neurogenesis. Maternal obesity impairs neurogenesis by reducing cell proliferation, increasing neuronal marker expression, and shifting development toward astrogliogenesis. Differentially expressed genes revealed disruptions in key developmental signaling pathways and reduced AKT phosphorylation, particularly at E14.5. These changes were associated with epigenetic alterations, mainly the differential expression and phosphorylation of EZH2 and subsequent changes in global histone modifications. Chromatin immunoprecipitation sequencing 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 high-fat diet embryos along with increased association with AMPK-Thr172 in accordance with previous studies showing that Ampk catalyzes EZH2-Thr311p. These results suggest that an epigenetic gene regulatory mechanism mediated by Ampk and Ezh2 interactions resulted in reduced H3K27me3 and derepression of key developmental genes, which could have led to cell fate changes observed in the developing embryo brain cortex due to maternal obesity.