Cell-type-specific m1A dynamics are associated with microglial phenotypic transition and neuronal metabolic adaptation during spinal cord injury.

Abstract

m1A (N1-methyladenosine) is an important epigenetic mechanism that regulates the onset and progression of many diseases, including spinal cord injury (SCI). To investigate the overall changes in m1A following SCI, we analyzed transcriptomic sequencing data from SCI samples and assigned m1A scores based on the levels of m1A regulatory factors. In this study, the m1A score is an inferred proxy calculated from the expression of m1A regulator genes (writers/erasers/readers). It does not directly measure RNA m1A modification levels. Our results show that the m1A score increased within the first day after SCI and then decreased, falling below baseline by day 3 and day 7. Further analysis revealed that microglia and neurons are the two cell types with the most significant changes in the m1A score. In microglia, m1A score decreased at all time points, whereas in neurons, m1A score increased at all time points. Additionally, pseudotime and functional enrichment analyses suggested that the m1A score is associated with microglial phenotypic transition and neuronal energy metabolism, which was further validated by both in vivo and in vitro experiments. In summary, our study unveils the characteristic changes of m1A at both the bulk and single-cell levels following SCI, and suggests potential links to neuronal function and supports the rationale for further studies exploring m1A-related regulators as therapeutic targets in SCI.