Jiang Jie, Srivastava Sankalp, Liu Sheng, Seim Gretchen, Claude Rodney, Zhong Minghua, Cao Sha, Davé Utpal, Kapur Reuben, Mosley Amber L, Zhang Chi, Wan Jun, Fan Jing, Zhang Ji
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
iScience. 2023 Mar 16;26(4):106425. doi: 10.1016/j.isci.2023.106425. eCollection 2023 Apr 21.
Intracellular α-ketoglutarate is an indispensable substrate for the Jumonji family of histone demethylases (JHDMs) mediating most of the histone demethylation reactions. Since α-ketoglutarate is an intermediate of the tricarboxylic acid cycle and a product of transamination, its availability is governed by the metabolism of several amino acids. Here, we show that asparagine starvation suppresses global histone demethylation. This process is neither due to the change of expression of histone-modifying enzymes nor due to the change of intracellular levels of α-ketoglutarate. Rather, asparagine starvation reduces the intracellular pool of labile iron, a key co-factor for the JHDMs to function. Mechanistically, asparagine starvation suppresses the expression of the transferrin receptor to limit iron uptake. Furthermore, iron supplementation to the culture medium restores histone demethylation and alters gene expression to accelerate cell death upon asparagine depletion. These results suggest that suppressing iron-dependent histone demethylation is part of the cellular adaptive response to asparagine starvation.
细胞内的α-酮戊二酸是Jumonji家族组蛋白去甲基化酶（JHDMs）介导大多数组蛋白去甲基化反应所必需的底物。由于α-酮戊二酸是三羧酸循环的中间产物和转氨基作用的产物，其可用性受几种氨基酸代谢的调控。在此，我们表明天冬酰胺饥饿会抑制整体组蛋白去甲基化。这个过程既不是由于组蛋白修饰酶表达的变化，也不是由于细胞内α-酮戊二酸水平的变化。相反，天冬酰胺饥饿会减少不稳定铁的细胞内储备，而不稳定铁是JHDMs发挥功能的关键辅助因子。从机制上讲，天冬酰胺饥饿会抑制转铁蛋白受体的表达以限制铁的摄取。此外，向培养基中补充铁可恢复组蛋白去甲基化，并改变基因表达以加速天冬酰胺耗尽时的细胞死亡。这些结果表明，抑制铁依赖性组蛋白去甲基化是细胞对天冬酰胺饥饿的适应性反应的一部分。
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