Mettl3-dependent m6A 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. The brain is vulnerable to stress and disease, with much work focused on defining mechanisms that impact the brain’s resilience. Here the author’s reveal in Drosophila that m 6 A epitranscriptomic modification of RNA dampens the brain’s capacity to mitigate stress by regulating RNA stability and translation.