Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes.
Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes.
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异染色质通过沉默 p53 靶基因保护视网膜色素上皮细胞免受氧化损伤
DOI：
10.1073/pnas.1715237115
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发表时间：
2018-04-24
影响因子：
11.1
通讯作者：
Li DW
中科院分区：
文献类型：
--
作者：
Gong L;Liu F;Xiong Z;Qi R;Luo Z;Gong X;Nie Q;Sun Q;Liu YF;Qing W;Wang L;Zhang L;Tang X;Huang S;Li G;Ouyang H;Xiang M;Nguyen QD;Liu Y;Li DW
氧化应激诱导的视网膜色素上皮（RPE）细胞损伤与老年性黄斑变性（AMD）的发病机制密切相关，AMD是老年人失明的主要原因。在这里，我们报道氧化应激诱导的异染色质形成对促进RPE存活至关重要。在机制上，氧化损伤诱导的异染色质形成发生在凋亡基因的53个靶启动子上，并受p53 sumoylation调节。我们的研究证明了染色质构象、p53聚合化和RPE细胞死亡之间的机制联系。我们提出靶向异染色质为AMD治疗提供了一种新的策略。氧化应激（OS）诱导的视网膜色素上皮（RPE）细胞凋亡与老年性黄斑变性（AMD）的发病机制密切相关，AMD是老年人失明的主要原因。异染色质是一种致密的、转录惰性的染色质结构，最近被证明在应激刺激下是动态调节的。然而，异染色质对OS暴露的功能机制尚不清楚。本研究表明，OS增加了体内和体外异染色质的形成，这对于保护RPE细胞免受氧化损伤至关重要。在机制上，os诱导的异染色质选择性地积聚在p53调控的促凋亡靶启动子上，并抑制它们的转录。此外，os诱导的p53去氧基化促进p53 -异染色质相互作用并调节p53启动子选择，导致异染色质的基因座特异性募集和转录抑制。总之，我们的研究结果证明了os诱导的异染色质形成的保护功能，其中p53脱苏化引导的启动子选择和随后的异染色质募集发挥了关键作用。我们提出，靶向异染色质为治疗AMD提供了一种可行的治疗策略。
Significance Oxidative stress-induced damage to retinal pigmented epithelial (RPE) cells is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Here we report that oxidative stress-induced heterochromatin formation is essential to promote RPE survival. Mechanistically, oxidative damage-induced formation of heterochromatin occurs at the 53 target promoters of apoptosis genes and is regulated by p53 sumoylation. Our study demonstrates mechanistic links among chromatin conformation, p53 sumoylation, and RPE cell death. We propose that targeting heterochromatin provides a novel strategy for AMD treatment. Oxidative stress (OS)-induced retinal pigment epithelium (RPE) cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Heterochromatin, a compact and transcriptional inert chromatin structure, has been recently shown to be dynamically regulated in response to stress stimuli. The functional mechanism of heterochromatin on OS exposure is unclear, however. Here we show that OS increases heterochromatin formation both in vivo and in vitro, which is essential for protecting RPE cells from oxidative damage. Mechanistically, OS-induced heterochromatin selectively accumulates at p53-regulated proapoptotic target promoters and inhibits their transcription. Furthermore, OS-induced desumoylation of p53 promotes p53–heterochromatin interaction and regulates p53 promoter selection, resulting in the locus-specific recruitment of heterochromatin and transcription repression. Together, our findings demonstrate a protective function of OS-induced heterochromatin formation in which p53 desumoylation-guided promoter selection and subsequent heterochromatin recruitment play a critical role. We propose that targeting heterochromatin provides a plausible therapeutic strategy for the treatment of AMD.
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抵抗视网膜色素上皮的氧化应激和损伤的机制。
DOI：
10.1016/b978-0-12-394309-5.00004-3
发表时间：
2012
影响因子：
--
作者：
Plafker, Scott M.;O'Mealey, Gary B.;Szweda, Luke I.
通讯作者：
Szweda, Luke I.
影响因子：
16
作者：
Sen, Nirmalya;Kumari, Rajni;Das, Sanjeev
通讯作者：
Das, Sanjeev
影响因子：
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作者：
Gostissa, M;Hengstermann, A;Del Sal, G
通讯作者：
Del Sal, G
影响因子：
11.4
作者：
Rodriguez, MS;Desterro, JMP;Hay, RT
通讯作者：
Hay, RT
影响因子：
3.4
作者：
Fuhrmann, Sabine;Zou, ChangJiang;Levine, Edward M.
通讯作者：
Levine, Edward M.