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

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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.
Funding Information
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35-GM133721, T32-GM007229, R35-GM133721)
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (F31-AG063470)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

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