Long Noncoding RNA OIP5-AS1 Promotes Cell Apoptosis and Cataract Formation by Blocking POLG Expression Under Oxidative Stress

Abstract

Purpose 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. Methods 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. Results OIP5-AS1 was upregulated in cataract lenses and B3 cells under oxidative stress. OIP5-AS1 knockdown protected B3 cells from H 2 O 2 -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. Conclusions 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.

Long non‐coding RNA OIP5‐AS1 (Cyrano): A context‐specific regulator of normal and disease processes

“…OIP5‐AS1 has been implicated in the development of cataracts, where under oxidative stress, it is activated by TFAP2A and upregulated in B3 cells and lens epithelial cells 73 . Knockdown of OIP5‐AS1 resulted in a reduction of B3 cell apoptosis due to H 2 O 2 ‐induced oxidative stress, as well as an absence of lens opacity under oxidative stress, all of which contribute to the development of cataracts 73 .…”

“…OIP5‐AS1 has been implicated in the development of cataracts, where under oxidative stress, it is activated by TFAP2A and upregulated in B3 cells and lens epithelial cells 73 . Knockdown of OIP5‐AS1 resulted in a reduction of B3 cell apoptosis due to H 2 O 2 ‐induced oxidative stress, as well as an absence of lens opacity under oxidative stress, all of which contribute to the development of cataracts 73 . The hypothesis is that OIP5‐AS1 contributes to regulation of the HuR‐mediated mitochondrial apoptosis pathway in B3 cells by mediating the destruction of POLG mRNA in the presence of oxidative stress, which could support the eventual development of cataracts 73 …”

Reactive Oxygen Species and Eye Aging in Cataracts through Biomolecular Mechanisms

“…Cyrano a lncRNA namely OIP5-AS1 works in vivo as an up-regulating system, with the capacity of renewal embryonic stem cells, modulating miR7 MicroRNAs (miRNAs, miR), capable of regulating post-transcriptional gene expressions; disproportion in the miRNA network has been associated with the development of many pathological conditions and diseases, including not only cataracts but cancer [86][87][88][89].…”

Hypoxic condition induced H3K27me3 modification of the LncRNA Tmem235 promoter thus supporting apoptosis of BMSCs

“…Studies have found that although long non-coding RNAs (LncRNAs) cannot directly encode proteins, they can regulate the expression of apoptosis-related genes before, during, and after gene transcription, thereby interfering with apoptosis [11][12][13][14]. To determine which LncRNAs are related to the hypoxic apoptosis of BMSCs, we used LncRNA chip combined with bioinformatics analysis.…”