Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
Cell Death Dis. 2019 Feb 27;10(3):198. doi: 10.1038/s41419-019-1434-3.
Cellular metabolism plays a crucial role in controlling the proliferation, differentiation, and quiescence of neural stem cells (NSCs). The metabolic transition from aerobic glycolysis to oxidative phosphorylation has been regarded as a hallmark of neuronal differentiation. Understanding what triggers metabolism reprogramming and how glucose metabolism directs NSC differentiation may provide new insight into the regenerative potential of the brain. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is an endogenous inhibitor of glycolysis and is highly expressed in mature neurons. However, its function in embryonic NSCs has not yet been explored. In this study, we aimed to investigate the precise roles of TIGAR in NSCs and the possible involvement of metabolic reprogramming in the TIGAR regulatory network. We observed that TIGAR is significantly increased during brain development as neural differentiation proceeds, especially at the peak of NSC differentiation (E14.5-E16.5). In cultured NSCs, knockdown of TIGAR reduced the expression of microtubule-associated protein 2 (MAP2), neuron-specific class III beta-tubulin (Tuj1), glial fibrillary acidic protein (GFAP), Ngn1, and NeuroD1, and enhanced the expression of REST, suggesting that TIGAR is an important regulator of NSC differentiation. Furthermore, TIGAR enhanced the expression of lactate dehydrogenase B (LDHB) and the mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) markers, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1α), nuclear respiratory factor (NRF1), and MitoNEET during NSC differentiation. TIGAR can decrease lactate production and accelerate oxygen consumption and ATP generation to maintain a high rate of OXPHOS in differentiated NSCs. Interestingly, knockdown of TIGAR decreased the level of acetyl-CoA and H3K9 acetylation at the promoters of Ngn1, Neurod1, and Gfap. Acetate, a precursor of acetyl-CoA, increased the level of H3K9 acetylation and rescued the effect of TIGAR deficiency on NSC differentiation. Together, our data demonstrated that TIGAR promotes metabolic reprogramming and regulates NSC differentiation through an epigenetic mechanism.
细胞代谢在控制神经干细胞（NSCs）的增殖、分化和静止中起着至关重要的作用。从有氧糖酵解到氧化磷酸化的代谢转变被认为是神经元分化的标志。了解触发代谢重编程的原因以及葡萄糖代谢如何指导 NSC 分化，可能为大脑的再生潜力提供新的见解。TP53 诱导的糖酵解和凋亡调节剂（TIGAR）是糖酵解的内源性抑制剂，在成熟神经元中高度表达。然而，其在胚胎 NSCs 中的功能尚未被探索。在这项研究中，我们旨在研究 TIGAR 在 NSCs 中的精确作用，以及代谢重编程在 TIGAR 调控网络中的可能参与。我们观察到，TIGAR 在大脑发育过程中随着神经分化的进行而显著增加，特别是在 NSC 分化的高峰期（E14.5-E16.5）。在培养的 NSCs 中，TIGAR 的敲低降低了微管相关蛋白 2（MAP2）、神经元特异性 III 类β-微管蛋白（Tuj1）、神经胶质纤维酸性蛋白（GFAP）、Ngn1 和 NeuroD1 的表达，同时增强了 REST 的表达，表明 TIGAR 是 NSC 分化的重要调控因子。此外，TIGAR 增强了乳酸脱氢酶 B（LDHB）和线粒体生物发生和氧化磷酸化（OXPHOS）标志物、过氧化物酶体增殖物激活受体γ共激活因子 1（PGC-1α）、核呼吸因子（NRF1）和 MitoNEET 的表达在 NSC 分化过程中。TIGAR 可以减少乳酸的产生，加速氧气消耗和 ATP 的产生，以维持分化 NSCs 中高的 OXPHOS 速率。有趣的是，TIGAR 的敲低降低了 Ngn1、Neurod1 和 Gfap 启动子上的乙酰辅酶 A 水平和 H3K9 乙酰化水平。乙酰辅酶 A 的前体——乙酸增加了 H3K9 乙酰化水平，并挽救了 TIGAR 缺陷对 NSC 分化的影响。总之，我们的数据表明，TIGAR 通过表观遗传机制促进代谢重编程并调节 NSC 分化。
