Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53
Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53
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H2B 单泛素化和 p53 对铁死亡的表观遗传调控
DOI：
10.15252/embr.201847563
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发表时间：
2019-07-01
期刊：
影响因子：
7.7
通讯作者：
Chen, Su
中科院分区：
文献类型：
--
作者：
Wang, Yufei;Yang, Lu;Chen, Su
组蛋白H_2B与赖氨酸120(H_2Bub1)结合是一种表观遗传标记，通常与转录激活有关，但H_2Bub1的整体功能尚不清楚。铁下垂是一种非凋亡性细胞死亡，其特征是铁依赖过量产生脂质过氧化氢，这可以被溶质载体家族成员11(SLC7A11/XCT)的抗氧化活性所抑制，SLC7A11/XCT是胱氨酸/谷氨酸逆向转运体的一个组成部分。核事件是否参与铁下垂的调节在很大程度上是未知的。在这里，我们证明了在Erastin诱导的铁性下垂过程中，H_2Bub1的水平降低，并且H_2Bub_1的丢失增加了细胞对铁性下垂的敏感性。H2Bub1在表观遗传学上激活SLC7A11的表达。此外，我们还发现，肿瘤抑制因子P53通过促进脱泛素酶USP7的核转位，独立于P53‘S转录因子活性，负向调节H_2Bub1水平。此外，我们的研究表明，在erastin治疗过程中，p53减少了SLC7A11基因调控区的H2Bub1占有率，并抑制了SLC7A11的表达。这些数据不仅表明了P53在染色质调节中的非典型性作用，而且还通过H_2Bub1介导的表观遗传途径将P53与铁性下垂联系起来。总体而言，我们的工作揭示了一种以前未被认识的调节铁性下垂的表观遗传机制。
Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. Ferroptosis is a form of non-apoptotic cell death characterized by the iron-dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin-induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1-mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis.