METTL3 regulates hippocampal gene transcription via N6-methyladenosine methylation in sevoflurane-induced...

Area of Science:

• Neuroscience
• Epigenetics
• Anesthesiology

Background:

• Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients undergoing surgery, significantly influenced by anesthesia.
• N6-methyladenosine (m6A) RNA methylation, an epigenetic mechanism regulating gene expression, has not been previously investigated in the context of POCD.

Purpose of the Study:

• To investigate the role of m6A RNA methylation in sevoflurane-induced POCD in elderly mice.
• To elucidate the underlying molecular mechanisms involving m6A modification and its associated proteins.

Main Methods:

• Construction of elderly POCD mouse models using sevoflurane exposure.
• Global m6A RNA methylation analysis in hippocampal tissues.
• RNA immunoprecipitation sequencing (RIP-Seq) to identify m6A-modified genes.
• Western blotting and RIP-qPCR assays to assess m6A-related proteins and METTL3 binding.
• Analysis of the MAPK/ERK pathway activation.

Main Results:

• Sevoflurane exposure led to compromised global m6A RNA methylation in the hippocampus of elderly mice.
• RIP-Seq identified significant alterations in m6A methylation in the 5'UTRs of specific genes, including decreased methylation in SOX2, SYN1, and BDNF, and increased methylation in BACE1 and IL17A.
• No significant differences were observed in the expression of m6A 'writers', 'erasers', or 'readers'.
• Sevoflurane weakened the binding affinity of METTL3 on mRNA 5'UTRs and reduced METTL3 phosphorylation by inactivating the MAPK/ERK pathway.

Conclusions:

• Sevoflurane-induced inactivation of METTL3 in the mouse hippocampus, mediated by MAPK/ERK pathway suppression, perturbs m6A RNA methylation signals.
• This perturbation in m6A methylation is implicated in the pathogenesis of POCD.
• The findings highlight a novel epigenetic mechanism contributing to anesthesia-related cognitive impairment.