Long Noncoding RNA OIP5-AS1 Promotes Cell Apoptosis and Cataract Formation by Blocking POLG Expression Under Oxidative Stress.
Long Noncoding RNA OIP5-AS1 Promotes Cell Apoptosis and Cataract Formation by Blocking POLG Expression Under Oxidative Stress.
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长非编码 RNA OIP5-AS1 通过在氧化应激下阻断 POLG 表达来抑制细胞凋亡和白内障形成
DOI：
10.1167/iovs.61.12.3
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发表时间：
2020-10-01
影响因子：
4.4
通讯作者：
Pei C
中科院分区：
文献类型：
--
作者：
Jing R;Ma B;Qi T;Hu C;Liao C;Wen C;Shao Y;Pei C
白内障是一种人工晶状体混浊，是导致失明的主要原因。晶状体表达的长链非编码RNA OIP5-AS1在白内障患者晶状体上皮细胞中表达上调，提示其在白内障发病中的作用。我们研究了OIP5-AS1在白内障发生中的调控作用，以及潜在的RNA结合蛋白、下游靶基因和上游转录因子。采用临床胶囊和体外白内障模型检测OIP5-AS1的表达。采用Western blots、JC-1染色、流式细胞术检测细胞凋亡。核糖核蛋白免疫沉淀- qpcr证实OIP5-AS1与POLG的相互作用。采用染色质免疫沉淀- qpcr检测TFAP2A与OIP5-AS1启动子区的结合情况。氧化应激下，OIP5-AS1在白内障晶状体和B3细胞中表达上调。OIP5-AS1敲低可保护体外白内障模型中h2o2诱导的B3细胞凋亡，减轻晶状体混浊。HuR作为携带OIP5-AS1和POLG mRNA的支架，介导POLG mRNA的降解。POLG在白内障晶状体和氧化应激B3细胞中下调，POLG的缺失降低了mtDNA拷贝数和MMP，增加了活性氧的产生，并使B3细胞对氧化应激诱导的凋亡敏感。POLG过表达逆转了这些影响。TFAP2A结合OIP5-AS1启动子，参与OIP5-AS1的表达。我们发现，经TFAP2A激活的OIP5-AS1通过抑制HuR介导的POLG表达参与白内障的形成，从而导致晶状体上皮细胞凋亡增加，晶状体混浊加重，提示OIP5-AS1是白内障治疗的潜在靶点。
Cataract, a clouding of the intraocular lens, is the leading cause of blindness. The lens-expressed long noncoding RNA OIP5-AS1 was upregulated in lens epithelial cells from patients with cataracts, suggesting its pathogenic role in cataracts. We investigated the regulatory role of OIP5-AS1 in the development of cataracts as well as potential RNA binding proteins, downstream target genes, and upstream transcription factors. Clinical capsules and ex vivo and in vitro cataract models were used to test OIP5-AS1 expression. Cell apoptosis was detected using Western blots, JC-1 staining, and flow cytometry. Ribonucleoprotein immunoprecipitation-qPCR was performed to confirm the interaction of OIP5-AS1 and POLG. Chromatin immunoprecipitation-qPCR was used to determine the binding of TFAP2A and the OIP5-AS1 promoter region. OIP5-AS1 was upregulated in cataract lenses and B3 cells under oxidative stress. OIP5-AS1 knockdown protected B3 cells from H2O2-induced apoptosis and alleviated lens opacity in the ex vivo cataract model. HuR functioned as a scaffold carrying OIP5-AS1 and POLG mRNA and mediated the decay of POLG mRNA. POLG was downregulated in the cataract lens and oxidative-stressed B3 cells, and POLG depletion decreased the mtDNA copy number and MMP, increased reactive oxygen species production, and sensitized B3 cells to oxidative stress-induced apoptosis. POLG overexpression reversed these effects. TFAP2A bound the OIP5-AS1 promoter and contributed to OIP5-AS1 expression. We demonstrated that OIP5-AS1, activated by TFAP2A, contributed to cataract formation by inhibiting POLG expression mediated by HuR, thus leading to increased apoptosis of lens epithelial cells and aggravated lens opacity, suggesting that OIP5-AS1 is a potential target for cataract treatment.
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影响因子：
4.4
作者：
Formichi, Patrizia;Radi, Elena;Federico, Antonio
通讯作者：
Federico, Antonio
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影响因子：
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作者：
Kim J;Noh JH;Lee SK;Munk R;Sharov A;Lehrmann E;Zhang Y;Wang W;Abdelmohsen K;Gorospe M
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影响因子：
14.9
作者：
Khan A;Fornes O;Stigliani A;Gheorghe M;Castro-Mondragon JA;van der Lee R;Bessy A;Chèneby J;Kulkarni SR;Tan G;Baranasic D;Arenillas DJ;Sandelin A;Vandepoele K;Lenhard B;Ballester B;Wasserman WW;Parcy F;Mathelier A
通讯作者：
Mathelier A
影响因子：
3.5
作者：
Bekheirnia, Mir Reza;Zhang, Wei;Dhar, Shweta U.
通讯作者：
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影响因子：
3.5
作者：
Hu, Guo-wen;Wu, Lei;Lang, Hai-li
通讯作者：
Lang, Hai-li