Mettl3-dependent m⁶A modification attenuates the brain stress response in Drosophila.

Abstract

N⁶-methyladenosine (m⁶A), the most prevalent internal modification on eukaryotic mRNA, plays an essential role in various stress responses. The brain is uniquely vulnerable to cellular stress, thus defining how m⁶A sculpts the brain's susceptibility may provide insight to brain aging and disease-related stress. Here we investigate the impact of m⁶A mRNA methylation in the adult Drosophila brain with stress. We show that m⁶A is enriched in the adult brain and increases with heat stress. Through m⁶A-immunoprecipitation sequencing, we show 5'UTR Mettl3-dependent m⁶A is enriched in transcripts of neuronal processes and signaling pathways that increase upon stress. Mettl3 knockdown results in increased levels of m⁶A targets and confers resilience to stress. We find loss of Mettl3 results in decreased levels of nuclear m⁶A reader Ythdc1, and knockdown of Ythdc1 also leads to stress resilience. Overall, our data suggest that m⁶A modification in Drosophila dampens the brain's biological response to stress.