Altered N6-Methyladenosine Modification Patterns and Transcript Profiles Contributes to Cognitive Dysfunction in...

N6-methyladenosine (m⁶A) constitutes the paramount post-transcriptional modification within eukaryotic mRNA. This modification is subjected to stimulus-dependent regulation within the central nervous system of mammals, being influenced by sensory experiences, learning processes, and injuries. The patterns of m⁶A methylation within the hippocampal region of diabetes cognitive impairment (DCI) has not been investigated. A DCI model was established by feeding a high-fat diet to C57BL/6J mice. m⁶A and RNA sequencing was conducted to profile the m⁶A-tagged transcripts in the hippocampus. Methylated RNA immunoprecipitation with next-generation sequencing and RNA sequencing analyses yielded differentially m⁶A-modified and expressed genes in the hippocampus of DCI mice, which were enriched in pathways involving synaptic transmission and axonal guidance. Mechanistic analyses revealed a remarkable change in m⁶A modification levels through alteration of the mRNA expression of m⁶A methyltransferases (METTL3 and METTL14) and demethylase (FTO) in the hippocampus of DCI mice. We identified a co-mediated specific RNA regulatory strategy that broadens the epigenetic regulatory mechanism of RNA-induced neurodegenerative disorders associated with metabolic and endocrine diseases.