The landscape of m¹A modification and its posttranscriptional regulatory functions in primary neurons.

Abstract

Cerebral ischaemia‒reperfusion injury (IRI), during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m¹A) is an RNA modification that can affect gene expression and RNA stability. The m¹A landscape and potential functions of m¹A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m¹A modification in normal and OGD/R-treated mouse neurons and the effect of m¹A on diverse RNAs. We investigated the m¹A landscape in primary neurons, identified m¹A-modified RNAs, and found that OGD/R increased the number of m¹A RNAs. m¹A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA-RNA binding proteins (RBPs) interactions and circRNA translation. We showed that m¹A modification mediates the circRNA/lncRNA‒miRNA-mRNA competing endogenous RNA (ceRNA) mechanism and that 3' untranslated region (3'UTR) modification of mRNAs can hinder miRNA-mRNA binding. Three modification patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m¹A-regulatory specificity. Systematic analysis of the m¹A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA modification and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology-related diseases.