Stroke triggers dynamic mA reprogramming of cerebral circular RNAs.

We previously showed that stroke alters circular RNA (circRNA) expression profiles. Many circRNAs undergo epitranscriptomic modifications, particularly methylation of adenosine to form N-methyladenosine (mA). This modification significantly influences the circRNA metabolism and functionality. Hence, we currently evaluated if transient focal ischemia in adult C57BL/6J mice alters the mA methylation of circRNAs. Changes in mA were profiled in the peri-infarct cortex following immunoprecipitation coupled with microarrays. Correlation and gene ontology analyses were performed to understand the association of mA changes with circRNA regulation and functional implications after stroke. Many circRNAs showed differential regulation (up or down) after stroke, and this change was highest at 24h of reperfusion. Notably, most circRNAs differentially regulated after stroke also exhibited temporal changes in mA modification patterns. The majority of circRNAs that showed post-stroke differential mA modifications were derived from protein-coding genes. Hyper-than hypomethylation of circRNAs was most prevalent after stroke. Gene ontology analysis of the host genes suggested that mA-modified circRNAs might regulate functions such as synapse-related processes, indicating that mA epitranscriptomic modification in circRNAs could potentially influence post-stroke synaptic pathophysiology.