CRL4DCAF8 dependent opposing stability control over the chromatin remodeler LSH orchestrates epigenetic dynamics in ferroptosis
CRL4DCAF8 dependent opposing stability control over the chromatin remodeler LSH orchestrates epigenetic dynamics in ferroptosis
复制标题
CRL4（DCAF8）依赖的对染色质重塑剂的相反稳定性控制 LSH 协调铁死亡中的表观遗传动力学
DOI：
10.1038/s41418-020-00689-5
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发表时间：
2020-12-07
影响因子：
12.4
通讯作者：
Zhang, Yu
中科院分区：
文献类型：
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作者：
Huang, Daoyuan;Li, Qian;Zhang, Yu
尽管越来越多的证据表明铁死亡与多种病理有关，但氧化诱导剂和染色质之间的分子联系作为其繁殖的表观遗传记忆载体仍然难以捉摸。在这里，我们报道了两个WD40蛋白DCAF8和WDR76分别作为Cullin-4环泛素连接酶（CRL4）系统的底物适配器和分子抑制剂，用于染色质重塑者LSH的稳定性控制。降解分析和CRL4-DCAF8复合体重组表明，CRL4（DCAF8）是一个真正的LSH E3连接酶。相反，WDR76通过竞争性抑制holo-CRL4(DCAF8)-LSH复合物组装来拮抗DCAF8靶向的LSH蛋白水解。重要的是，这种相反的调控策略被用于脂质氢过氧化诱导的铁上吊，我们通过转录组上位分析确定了DCAF8/WDR76/LSH轴显著调控的关键氧化还原稳态基因。这种调节机制归因于DNA羟甲基化促进WDR76与LSH的相互作用，DCAF8与WDR76的比例增加，以对抗LSH，并伴随DNA氧化减少和ROS过量产生。对铁下垂基因启动子表观遗传动力学的评估显示，在脂质过氧化应激下，连接体组蛋白H1和lsh相关的转录抑制被协调地去除。结合WDR76和DCAF8操作驱动的表型，这些数据确定了DCAF8和WDR76通过DNA羟甲基化感知LSH降解控制的氧化损伤是铁死亡表观遗传调控的关键联系。
Despite the emerging evidence on ferroptosis implicated in diverse pathologies, molecular linkage between oxidative inducers and chromatin as epigenetic memory carrier for its propagation remains elusive. Here, we report the identification of two WD40 proteins DCAF8 and WDR76 as substrate adapter and molecular inhibitor respectively of the Cullin-4 RING ubiquitin ligase (CRL4) system for stability control of chromatin remodeler LSH. Degradation analysis and CRL4-DCAF8 complex reconstitution demonstrate that CRL4(DCAF8) is a bona fide E3 ligase for LSH. In contrast, WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of the holo-CRL4(DCAF8)-LSH complex assembly. Importantly, this opposing regulatory strategy is utilized in lipid hydroperoxide induced ferroptosis, where we identify key redox homeostasis genes significantly regulated by the DCAF8/WDR76/LSH axis through transcriptomic epistasis analysis. This regulation is mechanistically attributed to DNA hydroxymethylation fostered WDR76 interaction with LSH and increased ratio of DCAF8 to WDR76 for antagonistic LSH association accompanying decreased DNA oxidation along with ROS overproduction. Evaluation of epigenetic dynamics at ferroptosis gene promoters reveals linker histone H1- and LSH-associated transcriptional repression is coordinately removed upon lipid peroxidation stress. Together with the phenotypes driven by WDR76 and DCAF8 manipulations, these data identify DCAF8- and WDR76-adapted oxidative damage sensing through DNA hydroxymethylation for LSH degradation control as a crucial nexus in epigenetic regulation of ferroptosis.