Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Nat Commun. 2022 Sep 14;13(1):5387. doi: 10.1038/s41467-022-33085-3.
N-methyladenosine (mA), 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 mA sculpts the brain's susceptibility may provide insight to brain aging and disease-related stress. Here we investigate the impact of mA mRNA methylation in the adult Drosophila brain with stress. We show that mA is enriched in the adult brain and increases with heat stress. Through mA-immunoprecipitation sequencing, we show 5'UTR Mettl3-dependent mA is enriched in transcripts of neuronal processes and signaling pathways that increase upon stress. Mettl3 knockdown results in increased levels of mA targets and confers resilience to stress. We find loss of Mettl3 results in decreased levels of nuclear mA reader Ythdc1, and knockdown of Ythdc1 also leads to stress resilience. Overall, our data suggest that mA modification in Drosophila dampens the brain's biological response to stress.
N6-甲基腺苷（m6A）是真核 mRNA 上最普遍的内部修饰，在各种应激反应中发挥着重要作用。大脑对细胞应激特别敏感，因此，了解 m6A 如何影响大脑的易感性可能有助于深入了解与大脑衰老和疾病相关的应激。在这里，我们研究了 m6A mRNA 甲基化在成年果蝇大脑应激中的作用。我们发现 m6A 在成年大脑中富集，并随着热应激而增加。通过 m6A 免疫沉淀测序，我们发现 5'UTR Mettl3 依赖性 m6A 在应激时增加的神经元过程和信号通路转录本中富集。Mettl3 敲低导致 m6A 靶标水平升高，并赋予对应激的抗性。我们发现 Mettl3 的缺失导致核 m6A 读码器 Ythdc1 的水平降低，而 Ythdc1 的敲低也导致应激抗性。总的来说，我们的数据表明，果蝇中的 m6A 修饰减轻了大脑对应激的生物学反应。
