Alawathugoda Thilina T, Sheikh Muhammad Abid, Challagandla Anil Kumar, Dheen S Thameem, Emerald Bright Starling, Ansari Suraiya Anjum
Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
J Biol Chem. 2025 Feb;301(2):108173. doi: 10.1016/j.jbc.2025.108173. Epub 2025 Jan 10.
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.
神经发育障碍有着复杂的起源，在胚胎发育早期就会显现，并与复杂的基因调控动态相关。诸如高血糖或血脂异常等代谢环境紊乱，尤其是由于母体肥胖导致的，会对胚胎中枢神经系统的最佳发育构成威胁。越来越多的证据表明，孕期这些代谢异常可能会改变神经发生途径，从而使发育中的胎儿易患神经发育障碍。这种破坏可能发生的一个主要机制涉及组蛋白修饰的变化，这是由组蛋白修饰酶表达的波动或其底物的可用性变化引起的。在此，我们使用了在妊娠前和妊娠期间通过高脂饮食诱导的母体肥胖大鼠模型，来研究母体肥胖对胚胎皮质神经发生的细胞和分子影响。母体肥胖通过减少细胞增殖、增加神经元标志物表达以及使发育向星形胶质细胞生成转变来损害神经发生。差异表达基因揭示了关键发育信号通路的破坏以及AKT磷酸化的减少，特别是在胚胎发育第14.5天。这些变化与表观遗传改变有关，主要是EZH2的差异表达和磷酸化以及随后整体组蛋白修饰的变化。染色质免疫沉淀测序显示，由于母体肥胖而上调的基因处H3K27me3减少，这可能是由于EZH2在苏氨酸311处的表达减少和磷酸化增加所致。有趣的是，根据先前显示Ampk催化EZH2 - 苏氨酸311磷酸化的研究，在高脂饮食胚胎中EZH2还显示O - GlcNAcylation增加以及与AMPK - 苏氨酸172的结合增加。这些结果表明，由Ampk和Ezh2相互作用介导的表观遗传基因调控机制导致H3K27me3减少和关键发育基因的去抑制，这可能导致了由于母体肥胖在发育中的胚胎脑皮质中观察到的细胞命运变化。
