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Analysis of long non-coding RNA expression profiles following focal cerebral ischemia in mice.

ABSTRACT: Long noncoding RNAs (lncRNAs) have a variety of biological functions and play key roles in many diseases. However, the knowledge of lncRNA function during a stroke is limited. We analyzed the expression profiles of lncRNAs in the brain ischemic region of mice after a 45min middle cerebral artery occlusion (MCAO) with a 48h reperfusion. Gene ontology and pathway analysis were used to elucidate the potential functions of the differentially expressed mRNAs. A total of 255 lncRNAs (217 up-regulated and 38 down-regulated) and 894 mRNAs (870 up-regulated and 24 down-regulated) showed significantly altered expression in the ischemic brain compared to the sham controls (fold change ?>2, P?0.05). The gene ontology terms were mainly associated with neutrophil chemotaxis, positive regulation of inflammatory response, cell cycle, positive regulation of apoptotic process, and apoptotic process. The pathway analysis indicated that the mRNAs were mainly associated with inflammatory pathways. Additionally, the interactions between the differentially expressed lncRNAs and mRNAs are revealed by a dynamic lncRNA-mRNA network. Our findings provide an overview of aberrantly expressed lncRNAs in stroke and further broaden the understanding of stroke pathogenesis.

SUBMITTER: Liu C

PROVIDER: S-EPMC5955004 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Analysis of long non-coding RNA expression profiles following focal cerebral ischemia in mice.

Liu Cuiying C Yang Jian J Zhang Chencheng C Liu Menglei M Geng Xiaokun X Ji Xunming X Du Huishan H Zhao Heng H

Neuroscience letters 20171128

Long noncoding RNAs (lncRNAs) have a variety of biological functions and play key roles in many diseases. However, the knowledge of lncRNA function during a stroke is limited. We analyzed the expression profiles of lncRNAs in the brain ischemic region of mice after a 45min middle cerebral artery occlusion (MCAO) with a 48h reperfusion. Gene ontology and pathway analysis were used to elucidate the potential functions of the differentially expressed mRNAs. A total of 255 lncRNAs (217 up-regulated ...[more]

PMID: 29195908

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Project description:The brain endothelium is an important therapeutic target for the inhibition of cerebrovascular dysfunction in ischemic stroke. Previously, we documented the important regulatory roles of microRNAs in the cerebral vasculature, in particular the cerebral vascular endothelium. However, the functional significance and molecular mechanisms of other classes of non-coding RNAs in the regulation of cerebrovascular endothelial pathophysiology after stroke are completely unknown. Using RNA sequencing (RNA-seq) technology, we profiled long non-coding RNA (lncRNA) expressional signatures in primary brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD), an in vitro mimic of ischemic stroke conditions. After 16h of OGD exposure, the expression levels for 362 of the 10,677 lncRNAs analyzed changed significantly, including a total of 147 lncRNAs increased and 70 lncRNAs decreased by more than 2-fold. Among them, the most highly upregulated lncRNAs include Snhg12, Malat1, and lnc-OGD 1006, whereas the most highly downregulated lncRNAs include 281008D09Rik, Peg13, and lnc-OGD 3916. Alteration of the most highly upregulated/downregulated ODG-responsive lncRNAs was further confirmed in cultured BMECs after OGD as well as isolated cerebral microvessels in mice following transient middle cerebral artery occlusion (MCAO) and 24h reperfusion by the quantitative real-time PCR approach. Moreover, promoter analysis of altered ODG-responsive endothelial lncRNA genes by bioinformatics showed substantial transcription factor binding sites on lncRNAs, implying potential transcriptional regulation of those lncRNAs. These findings are the first to identify OGD-responsive brain endothelial lncRNAs, which suggest potential pathological roles for these lncRNAs in mediating endothelial responses to ischemic stimuli. Endothelial-selective lncRNAs may function as a class of novel master regulators in cerebrovascular endothelial pathologies after ischemic stroke.

Project description:Background and purposeReperfusion after transient cerebral ischemia causes severe damage to mitochondria; however, little is known regarding the continuous change in mitochondrial biogenesis during reperfusion. Mitochondrial biogenesis causes an increase in the individual mitochondrial mass of neurons and maintains their aerobic set-point in the face of declining function. The aim of this study was to examine mitochondrial biogenesis in the cortex during reperfusion following focal cerebral ischemia.MethodsMale Wistar rats were subjected to transient focal cerebral ischemia. The relative amount of cortical mitochondrial DNA was analyzed using quantitative real-time PCR at 0 h, 24 h, 72 h, and 7 d after reperfusion. Three critical transcriptional regulators of mitochondrial biogenesis were measured by semi-quantitative reverse-transcription PCR. The protein expression of cytochrome C oxidase subunits I and IV was detected by Western blotting.ResultsEvidence of increased mitochondrial biogenesis was observed after reperfusion. The cortical mitochondrial DNA content increased after 24 h, peaked after 72 h, and maintained a high level for 7 d. The cortical expression of three critical genes for the transcriptional regulation of mitochondrial biogenesis, namely, peroxisome proliferator-activated receptor coactivator-1α, nuclear respiratory factor-1, and mitochondrial transcription factor A, also increased at 24 h and 72 h. The expression of peroxisome proliferator-activated receptor coactivator-1α returned to the baseline level at 7 d, but two other factors maintained higher levels compared with the controls. Moreover, the expression of cytochrome C oxidase subunits I and IV was increased in the cortex.ConclusionsThese results indicate that reperfusion increased mitochondrial biogenesis following focal cerebral ischemia, and this tendency was exacerbated as the reperfusion time was extended. Reperfusion-induced mitochondrial biogenesis was mediated through up-regulation of critical transcriptional regulators of mitochondrial biogenesis.

Dataset Information

Analysis of long non-coding RNA expression profiles following focal cerebral ischemia in mice.

Publications

Analysis of long non-coding RNA expression profiles following focal cerebral ischemia in mice.

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