Abstract
BackgroundN6-methyladenosine (m6A) is the most prevalent post-transcriptional modification of eukaryotic mRNA. It has been reported that there is a stimulus-dependent regulation of m6A in the mammalian central nervous system in response to sensory experience, learning, and injury. The mRNA m6A methylation pattern in rat cortex after traumatic brain injury (TBI) has not been investigated.ResultsIn this study, we conducted a genome-wide profiling of mRNA m6A methylation in rat cortex via methylated RNA immunoprecipitation sequencing (MeRIP-Seq). After TBI, the expressions of METTL14 and FTO were significantly down-regulated in rat cerebral cortex. Using MeRIP-Seq, we identified a total of 2165 significantly changed peaks, of which 1062 were significantly up-regulated and 1103 peaks were significantly down-regulated. These m6A peaks were located across 1850 genes. The analysis of both m6A peaks and mRNA expression revealed that there were 175 mRNA significantly altered methylation and expression levels after TBI. Moreover, it was found that functional FTO is necessary to repair neurological damage caused by TBI but has no effect on the spatial learning and memory abilities of TBI rats by using FTO inhibitor FB23–2.ConclusionThis study explored the m6A methylation pattern of mRNA after TBI in rat cortex and identified FTO as possible intervention targets in the epigenetic modification of TBI.
Highlights
N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification of eukaryotic mRNA
METTL14 and FTO were both down-regulated after traumatic brain injury (TBI) in rat cortex In order to investigate whether m6A methylation status was changed in rat cortex after TBI, we evaluated the six genes encoding methyltransferases and demethylases by quantitative reverse transcription polymerase chain reaction (qRT-PCR): METTL3, METTL14, WTAP, VIRMA, FTO, and ALKBH5
The expression changes of METTL14 and FTO could lead to a dynamic change in the m6A methylation in the rat cortex after TBI (Fig. 1)
Summary
N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification of eukaryotic mRNA. The mRNA m6A methylation pattern in rat cortex after traumatic brain injury (TBI) has not been investigated. A series of studies have found that epigenetic changes play important roles in TBI-induced pathophysiological responses such as DNA methylation, chromatin post-translational modifications, and miRNA regulation of gene expression [5, 9, 10]. TBI induced extensive changes in the DNA methylation patterns of rat hippocampus and the differentially methylated gene sites within 10 kb distance [16]. Another study investigated DNA methylation alterations after TBI in the rat frontal cortex using the brain blast-induced injury model and found that these differentially methylated genes were enrichet in cell death, survival, and nervous system development and function [17]
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