TIGAR promotes neural stem cell differentiation through acetyl-CoA- mediated histone acetylation
TIGAR promotes neural stem cell differentiation through acetyl-CoA- mediated histone acetylation
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TIGAR 通过乙酰辅酶 A 介导的组蛋白乙酰化促进神经干细胞分化
DOI：
10.1038/s41419-019-1434-3
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发表时间：
2019
影响因子：
9
通讯作者：
郝爱军
中科院分区：
文献类型：
--
作者：
周文娟;赵田田;杜静怡;姬光瑜;李心悦;纪淑芳;田文俞;王旭;郝爱军
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。了解是什么触发了代谢重编程以及葡萄糖代谢如何指导NSC分化，可能会为大脑的再生潜力提供新的见解。TP 53诱导型糖酵解和凋亡调节因子（TIGAR）是一种内源性糖酵解抑制剂，在成熟神经元中高度表达。然而，其在胚胎神经干细胞中的功能尚未被探索。在这项研究中，我们的目的是研究TIGAR在神经干细胞中的确切作用，以及TIGAR调控网络中代谢重编程的可能参与。我们观察到TIGAR在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（E14.5-E16.5）。在培养的NSC中，TIGAR的敲低降低了微管相关蛋白2（MAP 2）、神经元特异性III类β-微管蛋白（Tuj 1）、胶质细胞酸性蛋白（GFAP）、Ngn 1和NeuroD 1的表达，并增强了REST的表达，表明TIGAR是NSC分化的重要调节因子。此外，TIGAR增强了NSC分化过程中乳酸脱氢酶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（NRF 1）和MitoNEET的表达。TIGAR可以减少乳酸产生并加速氧消耗和ATP产生以维持分化的NSC中的高OXPHOS速率。有趣的是，TIGAR的敲低降低了Ngn 1、Neurod 1和GFap启动子处的乙酰辅酶A和H3 K9乙酰化水平。乙酰辅酶A的前体乙酸盐增加了H3 K9乙酰化的水平，并挽救了TIGAR缺乏对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。
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 ofNgn1,Neurod1, andGfap. 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.