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

N -methyladenosine (m 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 A sculpts the brain's susceptibility may provide insight to brain aging and diseas...

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Bibliographic Details
Published in:Nature communications 2022-09, Vol.13 (1), p.5387
Main Authors: Perlegos, Alexandra E, Shields, Emily J, Shen, Hui, Liu, Kathy Fange, Bonini, Nancy M
Format: Article
Language:English
Subjects:
Adenosine - metabolism
Animals
Brain - metabolism
Drosophila - genetics
Drosophila - metabolism
Methylation
RNA, Messenger - metabolism
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Summary:N -methyladenosine (m 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 A sculpts the brain's susceptibility may provide insight to brain aging and disease-related stress. Here we investigate the impact of m A mRNA methylation in the adult Drosophila brain with stress. We show that m A is enriched in the adult brain and increases with heat stress. Through m A-immunoprecipitation sequencing, we show 5'UTR Mettl3-dependent m A is enriched in transcripts of neuronal processes and signaling pathways that increase upon stress. Mettl3 knockdown results in increased levels of m A targets and confers resilience to stress. We find loss of Mettl3 results in decreased levels of nuclear m A reader Ythdc1, and knockdown of Ythdc1 also leads to stress resilience. Overall, our data suggest that m A modification in Drosophila dampens the brain's biological response to stress.
ISSN:2041-1723