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M6A modification of circSPECC1 attenuates age-related macular degeneration by resisting oxidative stress injuries and maintaining lipid metabolism in retinal pigment epithelium

ABSTRACT: Background: Retinal pigment epithelium (RPE) is the major site of pathological alterations in AMD, yet the mechanism governing its degeneration is poorly understood. Results: We found that expression of circSPECC1, a circular RNA derived from the SPECC1 gene, was down-regulated in RPE treated with oxidative stress and inflammation. CircSPECC1 insufficiency elevated mitochondrial superoxide in RPE, leading to oxidative stress induced RPE ferroptosis and depolarization. CircSPECC1 silencing also interfered RPE metabolism, causing irregular lipid metabolism and lipid accumulation. In mice, circSPECC1 deficiency leads to decreased visual ability, atrophic fundus presentations, as well as structural anomalies and reduced epithelial integrity in RPE. Moreover, retinal homeostasis was messed up upon circSPECC1 loss, as shown by photoreceptor dysfunction and microglia activation. Mechanically, decreased circSPECC1 expression in dysfunctional RPE was due to reduced N6-methyladenosine (m6A) levels of circSPECC1 transcript, which interrupted its back-splicing and circularization depending on m6A reader YTHDC1. CircSPECC1 regulated RPE features via directly sponging miR-145-5p to block its interaction with CDKN1A. Overexpressing miR-145-5p aggravated RPE dysfunctions in vivo and in vitro, mimicking effects of circSPECC1 silencing. Additionally, miR-145-5p inhibition alleviated RPE anomalies induced by circSPECC1 insufficiency, while miR-145-5p overexpression aggravated the retinal phenotypes. Conclusions: Collectively, circSPECC1, mediated by m6A modification and sponges miR-145-5p, resists oxidative stress injuries and maintains lipid metabolism in RPE. Pharmacological supplementation of circSPECC1, miR-145-5p inhibitor or m6A regulator is promising therapeutic option for atrophic retinopathies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197148 | GEO | 2022/02/25

REPOSITORIES: GEO

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Project description:Diabetic foot ulcers (DFUs) are one of the major complications of diabetes. Its molecular pathology remains poorly understood, impeding the development of effective treatments. Although it has been established that multiple cell types, including fibroblasts, keratinocytes, macrophages and endothelial cells, all contribute to inhibition of healing, less is known regarding individual contributions of each cell type. Thus, we generated primary fibroblasts from non-healing DFUs and evaluated their cellular and molecular properties in comparison to non-diabetic foot fibroblasts (NFFs). Specifically, we analyzed both micro-RNA and mRNA expression profiles of primary DFU fibroblasts. These paired genomic analyses identified a total of 331 reciprocal miRNA-mRNA pairs (21 miRNAs (FC>2.0) along with 239 predicted target genes (FC>1.5) that are significantly and differentially expressed. Of these, we focused on three miRNAs (miR-21-5p, miR-34a-5p, miR-145-5p) found to be induced in DFU fibroblasts as most differentially regulated. Their involvement in cellular functions important for wound healing was investigated by testing the expression of their downstream targets as well as by quantifying cellular behaviors in a prospectively collected and generated cell lines from 15 patients (7 DFUF and 8 NFF samples). We found large number of downstream targets of miR-21-5p, miR-34a-5p, miR-145-5p to be coordinately regulated in mRNA profiles, which was confirmed by qPCR. Genomic analysis of miR-21-5p, miR-34a-5p, miR-145-5p and their target genes indicates that these are contributing to the inhibition of cell movement and cell proliferation, together with increased cell differentiation and senescence in DFU fibroblasts, which was confirmed by cellular assays. We conclude that induction of miR-21-5p, miR-34a-5p, miR-145-5p in DFU dermal fibroblasts plays an important role in impairing multiple cellular functions, thus contributing to overall inhibition of healing in DFUs.

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M6A modification of circSPECC1 attenuates age-related macular degeneration by resisting oxidative stress injuries and maintaining lipid metabolism in retinal pigment epithelium

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