Mettl3-dependent m 6 A modification attenuates the brain stress response in Drosophila.

N 6 -methyladenosine (m 6 A), 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 m 6 A sculpts the brain's susceptibility may provide insight to brain aging and disease-related stress. Here we investigate the impact of m 6 A mRNA methylation in the adult Drosophila brain with stress. We show that m 6 A is enriched in the adult brain and increases with heat stress. Through m 6 A-immunoprecipitation sequencing, we show 5'UTR Mettl3-dependent m 6 A is enriched in transcripts of neuronal processes and signaling pathways that increase upon stress. Mettl3 knockdown results in increased levels of m 6 A targets and confers resilience to stress. We find loss of Mettl3 results in decreased levels of nuclear m 6 A reader Ythdc1, and knockdown of Ythdc1 also leads to stress resilience. Overall, our data suggest that m 6 A modification in Drosophila dampens the brain's biological response to stress.