Identification of microRNA-mRNA regulatory network associated with oxidative DNA damage in human astrocytes.

IF 3.9 4区 医学 Q2 NEUROSCIENCES ASN NEURO Pub Date : 2022-01-01 DOI:10.1177/17590914221101704
Chukwumaobim Daniel Nwokwu, Adam Y Xiao, Lynn Harrison, Gergana G Nestorova
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引用次数: 1

Abstract

The high lipid content of the brain, coupled with its heavy oxygen dependence and relatively weak antioxidant system, makes it highly susceptible to oxidative DNA damage that contributes to neurodegeneration. This study is aimed at identifying specific ROS-responsive miRNAs that modulate the expression and activity of the DNA repair proteins in human astrocytes, which could serve as potential biomarkers and lead to the development of targeted therapeutic strategies for neurological diseases. Oxidative DNA damage was established after treatment of human astrocytes with 10μM sodium dichromate for 16 h. Comet assay analysis indicated a significant increase in oxidized guanine lesions. RT-qPCR and ELISA assays confirmed that sodium dichromate reduced the mRNA and protein expression levels of the human base-excision repair enzyme, 8-deoxyguanosine DNA glycosylase 1 (hOGG1). Small RNAseq data were generated on an Ion Torrent™ system and the differentially expressed miRNAs were identified using Partek Flow® software. The biologically significant miRNAs were selected using miRNet 2.0. Oxidative-stress-induced DNA damage was associated with a significant decrease in miRNA expression: 231 downregulated miRNAs and 2 upregulated miRNAs (p < 0.05; >2-fold). In addition to identifying multiple miRNA-mRNA pairs involved in DNA repair processes, this study uncovered a novel miRNA-mRNA pair interaction: miR-1248:OGG1. Inhibition of miR-1248 via the transfection of its inhibitor restored the expression levels of hOGG1. Therefore, targeting the identified microRNA candidates could ameliorate the nuclear DNA damage caused by the brain's exposure to mutagens, reduce the incidence and improve the treatment of cancer and neurodegenerative disorders.

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与人星形胶质细胞DNA氧化损伤相关的microRNA-mRNA调控网络的鉴定。
大脑的高脂质含量,加上其严重的氧依赖性和相对较弱的抗氧化系统,使其极易受到氧化性DNA损伤,从而导致神经变性。本研究旨在鉴定人类星形胶质细胞中调节DNA修复蛋白表达和活性的特异性ros应答mirna,这些mirna可能作为潜在的生物标志物,并导致神经系统疾病的靶向治疗策略的发展。用10μM重铬酸钠处理人星形胶质细胞16小时后,发现氧化性DNA损伤显著增加。RT-qPCR和ELISA检测证实,重铬酸钠降低了人碱基切除修复酶8-脱氧鸟苷DNA糖基酶1 (hOGG1) mRNA和蛋白的表达水平。在Ion Torrent™系统上生成小rna - seq数据,并使用Partek Flow®软件鉴定差异表达的mirna。使用miRNet 2.0选择具有生物学意义的mirna。氧化应激诱导的DNA损伤与miRNA表达显著降低相关:231个miRNA下调,2个miRNA上调(p 2倍)。除了鉴定参与DNA修复过程的多个miRNA-mRNA对外,本研究还发现了一种新的miRNA-mRNA对相互作用:miR-1248:OGG1。通过转染其抑制剂抑制miR-1248,恢复hOGG1的表达水平。因此,靶向鉴定的候选microRNA可以改善大脑暴露于诱变剂引起的核DNA损伤,减少癌症和神经退行性疾病的发病率,改善治疗。
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来源期刊
ASN NEURO
ASN NEURO NEUROSCIENCES-
CiteScore
7.70
自引率
4.30%
发文量
35
审稿时长
>12 weeks
期刊介绍: ASN NEURO is an open access, peer-reviewed journal uniquely positioned to provide investigators with the most recent advances across the breadth of the cellular and molecular neurosciences. The official journal of the American Society for Neurochemistry, ASN NEURO is dedicated to the promotion, support, and facilitation of communication among cellular and molecular neuroscientists of all specializations.
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