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Published on: April 5, 2016
METTL3 Affects Spinal Cord Neuronal Apoptosis by Regulating Bcl-2 m6A Modifications After Spinal Cord Injury
Shengyu Guo1, Taotao Lin1, Gang Chen1
1Department of Orthopedics, Fujian Medical University Union Hospital, Fuzhou, China.
Objective:
Spinal cord injury (SCI) is a severe type of neurological trauma. N6-methyladenosine (m6A) modification is one of the most common internal modifications of RNA. The role of METTL3, the predominant methylation enzyme of m6A modification, in SCI remains unclear. This study aimed to investigate the role of methyltransferase METTL3 in SCI.
Methods:
After establishing the oxygen-glucose deprivation (OGD) model of PC12 cells and rat spinal cord hemisection model, we found that the expression of METTL3 and the overall m6A modification level were significantly increased in neurons. The m6A modification was identified on B-cell lymphoma 2 (Bcl-2) messenger RNA (mRNA) by bioinformatics analysis, and m6A-RNA immunoprecipitation and RNA immunoprecipitation. In addition, METTL3 was blocked by the specific inhibitor STM2457 and gene knockdown, and then apoptosis levels were measured.
Results:
In different models, we found that the expression of METTL3 and the overall m6A modification level were significantly increased in neurons. After inducing OGD, inhibition of METTL3 activity or expression increased the mRNA and protein levels of Bcl-2, inhibited neuronal apoptosis, and improved neuronal viability in the spinal cord.
Conclusion:
Inhibition of METTL3 activity or expression can inhibit the apoptosis of spinal cord neurons after SCI through the m6A/Bcl-2 signaling pathway.
Insights
Inhibition of METTL3, an enzyme involved in N6-methyladenosine (m6A) RNA modification, reduces spinal cord injury (SCI) related neuronal apoptosis. This finding highlights METTL3 as a potential therapeutic target for SCI treatment.
Area of Science:
- Neuroscience
- Molecular Biology
- Epigenetics
Background:
- Spinal cord injury (SCI) is a devastating neurological trauma.
- N6-methyladenosine (m6A) is a prevalent RNA modification.
- The role of METTL3, the primary m6A methyltransferase, in SCI is not well understood.
Purpose of the Study:
- To investigate the role of the methyltransferase METTL3 in spinal cord injury.
- To explore the potential of targeting METTL3 for SCI treatment.
Main Methods:
- Established oxygen-glucose deprivation (OGD) and rat spinal cord hemisection models.
- Assessed METTL3 expression and m6A modification levels.
- Utilized bioinformatics, m6A-RNA immunoprecipitation, and RNA immunoprecipitation.
- Inhibited METTL3 using STM2457 and gene knockdown to measure apoptosis.
Main Results:
- METTL3 expression and m6A levels were significantly elevated in neurons post-SCI.
- METTL3 inhibition increased Bcl-2 mRNA and protein levels.
- Inhibition of METTL3 reduced neuronal apoptosis and improved neuronal viability.
Conclusions:
- METTL3 inhibition mitigates spinal cord neuron apoptosis following SCI.
- The m6A/Bcl-2 signaling pathway is implicated in METTL3's effect on SCI.
- Targeting METTL3 presents a promising therapeutic strategy for SCI.
