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.

N ⁶ -甲基腺苷 (m ⁶ A) 是真核生物 mRNA 上最常见的内部修饰，在各种应激反应中发挥着重要作用。大脑特别容易受到细胞压力的影响，因此定义 m ⁶ A 如何塑造大脑的易感性可能有助于深入了解大脑衰老和疾病相关的压力。在这里，我们研究了压力下成年果蝇大脑中 m ⁶ A mRNA 甲基化的影响。我们发现，m ⁶ A 在成人大脑中丰富，并随着热应激而增加。通过 m ⁶ A 免疫沉淀测序，我们发现 5'UTR Mettl3依赖性 m ⁶ A 富含神经元过程和信号通路的转录本，这些转录本在应激时会增加。 Mettl3敲低导致 m ⁶ A 靶标水平增加，并赋予抗应激能力。我们发现Mettl3的缺失会导致核 m ⁶ A 阅读器Ythdc1水平下降，并且Ythdc1的敲除也会导致应激恢复能力。总体而言，我们的数据表明果蝇中的 m ⁶ A 修饰抑制了大脑对压力的生物反应。