Transient Focal Ischemia Significantly Alters the m6A Epitranscriptomic Tagging of RNAs in the Brain. Issue 10 (October 2019)

• Record Type: Journal Article
• Authors: Chokkalla, Anil K.; Mehta, Suresh L.; Kim, TaeHee; Chelluboina, Bharath; Kim, Jooyong; Vemuganti, Raghu
• Is Part Of: Stroke. Volume 50:Issue 10(2019)
• Publication Date: 2019-10
• Subjects: apoptosis -- inflammation -- m6A demethylase -- RNA Methylation; Cerebrovascular disease -- Periodicals; Cerebral circulation -- Periodicals; 616.81
• DOI: 10.1161/STROKEAHA.119.026433
• Languages: English
• ISSNs: 0039-2499

Abstract

Abstract : Background and Purpose—: Adenosine in many types of RNAs can be converted to m 6 A (N 6 -methyladenosine) which is a highly dynamic epitranscriptomic modification that regulates RNA metabolism and function. Of all organs, the brain shows the highest abundance of m 6 A methylation of RNAs. As recent studies showed that m 6 A modification promotes cell survival after adverse conditions, we currently evaluated the effect of stroke on cerebral m 6 A methylation in mRNAs and lncRNAs. Methods—: Adult C57BL/6J mice were subjected to transient middle cerebral artery occlusion. In the peri-infarct cortex, m 6 A levels were measured by dot blot analysis, and transcriptome-wide m 6 A changes were profiled using immunoprecipitated methylated RNAs with microarrays (44 122 mRNAs and 12 496 lncRNAs). Gene ontology analysis was conducted to understand the functional implications of m 6 A changes after stroke. Expression of m 6 A writers, readers, and erasers was also estimated in the ischemic brain. Results—: Global m 6 A levels increased significantly at 12 hours and 24 hours of reperfusion compared with sham. While 139 transcripts (122 mRNAs and 17 lncRNAs) were hypermethylated, 8 transcripts (5 mRNAs and 3 lncRNAs) were hypomethylated (>5-fold compared with sham) in the ischemic brain at 12 hours reperfusion. Inflammation, apoptosis, and transcriptional regulation are the major biological processes modulated by the poststroke differentially m 6 A methylated mRNAs. The m 6 A writers were unaltered, but the m 6 A eraser (fat mass and obesity-associated protein) decreased significantly after stroke compared with sham. Conclusions—: This is the first study to show that stroke alters the cerebral m 6 A epitranscriptome, which might have functional implications in poststroke pathophysiology. Abstract : Supplemental Digital Content is available in the text.