Abstract
AimThis study was conducted in order to reveal the alterations in the N6-methyladenosine (m6A) modification profile of cerebral ischemia–reperfusion injury model rats.Materials and MethodsRats were used to establish the middle cerebral artery occlusion and reperfusion (MCAO/R) model. MeRIP-seq and RNA-seq were performed to identify differences in m6A methylation and gene expression. The expression of m6A methylation regulators was analyzed in three datasets and detected by quantitative real-time polymerase chain reaction, western blot, and immunofluorescence.ResultsWe identified 1,160 differentially expressed genes with hypermethylated or hypomethylated m6A modifications. The differentially expressed genes with hypermethylated m6A modifications were involved in the pathways associated with inflammation, while hypomethylated differentially expressed genes were related to neurons and nerve synapses. Among the m6A regulators, FTO was specifically localized in neurons and significantly downregulated after MCAO/R.ConclusionOur study provided an m6A transcriptome-wide map of the MACO/R rat samples, which might provide new insights into the mechanisms of cerebral ischemia–reperfusion injury.
Highlights
As one of the most damaging neurological diseases, ischemic stroke (IS) accounts for approximately 80% of all strokes with a high risk of mortality and disability and affects approximately three million people in China (Jiang et al, 2016; Dabrowska-Bender et al, 2017; Wang et al, 2017)
We found that the total m6A levels were significantly increased compared with the sham group (p < 0.001), but there were no significant differences between the indicated time points in the middle cerebral artery occlusion and reperfusion (MCAO/R) group
Our results showed that m6A peaks were mainly enriched in the coding sequence (CDS), stop codon, and start codon in both groups (Figures 2D,E)
Summary
As one of the most damaging neurological diseases, ischemic stroke (IS) accounts for approximately 80% of all strokes with a high risk of mortality and disability and affects approximately three million people in China (Jiang et al, 2016; Dabrowska-Bender et al, 2017; Wang et al, 2017). Ischemic stroke is caused by a sudden disruption of blood flow to the brain, resulting in brain cell death and neurological deficits (Zhang et al, 2012). Intravenous thrombolysis and mechanical thrombectomy are approved therapies for the acute treatment of cerebral IS (Powers et al, 2019). CIRI usually causes malignant cerebral edema, blood–brain barrier disruption, and neuronal apoptosis (Liu et al, 2020). Over the past 40 years, basic experiments have revealed that the molecular mechanisms of CIRI involve multiple pathological processes, such as oxidative stress, apoptosis, inflammation, autophagy, and necrosis (Meng et al, 2018; Zhang et al, 2019). The neuroprotective strategies based on these mechanisms in clinical experiments have not yet provided the expected clinical outcomes (Barer and Berge, 2017), suggesting that there are other mechanisms by which CIRI affects the prognosis of patients with IS
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