Abstract
Long noncoding RNAs (lncRNAs) have important roles in various biological processes. Our previous work has revealed that dedifferentiation of retinal pigment epithelium (RPE) cells contributes to the pathology of age-related macular degeneration (AMD). Herein, we show roles of lncRNAs in RPE differentiation. We used microarray to identify lncRNA expression profiles in human induced pluripotent stem cells (hiPSCs) and hiPSC-derived RPE cells. A total of 217 differentially expressed lncRNAs along with the differentiation were initially identified, among which 13 lncRNAs showed a consistent fold change of over 2. LncRNA ZNF503-AS1, located in the cytoplasm of RPE cells, was found consistently upregulated along with RPE differentiation, and downregulated in the RPE-choroid of AMD patients. In vitro study further suggested that ZNF503-AS1 insufficiency could inhibit RPE differentiation, and promote its proliferation and migration. As ZNF503-AS1 is transcribed from the antisense strand of the ZNF503 gene locus, we further revealed its regulatory role in ZNF503 expression. ZNF503-AS1 was reversely correlated with ZNF503 expression. Our results also suggested that ZNF503 could inhibit RPE differentiation, and promote its proliferation and migration. Thus, ZNF503-AS1 potentially promotes RPE differentiation through downregulation of ZNF503 expression. In addition, nuclear factor-κB was recognized as a potential upstream transcript factor for ZNF503-AS1, which might participate in promoting RPE differentiation by regulating the expression of ZNF503-AS1. Taken together, our study identifies a group of RPE differentiation relevant lncRNAs, and the potential role of ZNF503-AS1 in the pathology of atrophic AMD, which might help with the intervention of AMD patients.
Highlights
Forms a part of the blood/retina barrier, secrets multiple growth factors, and is crucial in maintaining regular retinal functions.[2,3,4] Dysfunction and depletion of retinal pigment epithelium (RPE) cells are involved in multiple retinal degenerations, including agerelated macular degeneration (AMD).[2,5,6,7] AMD is a universal leading cause for irreversible vision loss in people aged over 55.8–10 Clinically, AMD can be classified into two major categories, namely atrophic and exudative AMD.[10]
Our study identifies a group of RPE differentiation relevant Long noncoding RNAs (lncRNAs), and the potential role of ZNF503-AS1 in the pathology of atrophic AMD, which might help with the intervention of AMD patients
We aim to reveal the roles of a lncRNA, ZNF503-AS1, in RPE differentiation, and to seek for a lncRNA-based potential therapeutic target for dry AMD
Summary
Forms a part of the blood/retina barrier, secrets multiple growth factors, and is crucial in maintaining regular retinal functions.[2,3,4] Dysfunction and depletion of RPE cells are involved in multiple retinal degenerations, including agerelated macular degeneration (AMD).[2,5,6,7] AMD is a universal leading cause for irreversible vision loss in people aged over 55.8–10 Clinically, AMD can be classified into two major categories, namely atrophic and exudative AMD.[10]. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides structurally homologous to proteincoding mRNAs, but has little or no protein-coding potential.[11] LncRNAs can modulate gene expressions as competing endogenous RNAs (ceRNAs).[11,12,13,14] The ceRNA hypothesis defines a microRNA (miRNA)-mediated posttranscriptional regulatory network In this network, proteincoding and non-protein-coding RNAs share one or more miRNA response elements and compete for miRNA binding, further modulating each other’s expressions.[12,15] LncRNAs have been reported to have regulatory roles in diverse biological processes, including cell differentiation, stem cell maintenance, and epigenetic regulation.[16,17,18] Dysregulation of lncRNAs is found involved in multiple human diseases such as cancer, neurological problems, and cardiovascular diseases.[19] Roles of lncRNAs in ocular diseases, such as diabetic retinopathy, proliferative vitreoretinopathy, glaucoma, ocular tumors, and ocular neovascularization, have been. We aim to reveal the roles of a lncRNA, ZNF503-AS1, in RPE differentiation, and to seek for a lncRNA-based potential therapeutic target for dry AMD
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