Related Experiment Video
Updated: Aug 28, 2025
A Rat Methyl-Seq Platform to Identify Epigenetic Changes Associated with Stress Exposure
Published on: October 24, 2018
Mettl3-dependent m6A modification attenuates the brain stress response in Drosophila
Alexandra E Perlegos1, Emily J Shields2,3,4, Hui Shen5
1Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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.
Insights
N6-methyladenosine (m6A) RNA modification in the Drosophila brain increases with heat stress. This m6A modification dampens the brain's biological response to stress, offering insights into brain aging and stress-related diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Epigenetics
Background:
- N6-methyladenosine (m6A) is a prevalent mRNA modification crucial for stress responses.
- The brain's vulnerability to cellular stress highlights the importance of understanding m6A's role in brain aging and disease.
- Investigating m6A in the Drosophila brain provides a model to study stress susceptibility.
Purpose of the Study:
- To investigate the impact of m6A mRNA methylation in the adult Drosophila brain under stress conditions.
- To elucidate the role of Mettl3 and Ythdc1 in m6A-mediated stress responses in the brain.
Main Methods:
- m6A-immunoprecipitation sequencing (m6A-IP-seq) to map m6A methylation sites.
- Analysis of m6A enrichment in specific transcripts and pathways.
- Genetic manipulation (knockdown) of Mettl3 and Ythdc1 to assess their function.
Main Results:
- m6A is enriched in the adult Drosophila brain and its levels increase with heat stress.
- Mettl3-dependent m6A is enriched in 5'UTRs of neuronal process and signaling pathway transcripts upregulated by stress.
- Mettl3 knockdown leads to increased m6A targets and confers stress resilience.
- Loss of Mettl3 reduces nuclear m6A reader Ythdc1 levels; Ythdc1 knockdown also confers stress resilience.
Conclusions:
- m6A modification in the Drosophila brain acts to dampen the biological response to stress.
- The Mettl3-Ythdc1 axis is a key regulator of m6A-mediated stress resilience in the brain.
- Understanding m6A regulation in the brain offers potential therapeutic targets for stress-related neurological disorders.
