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Updated: Aug 6, 2026
Characterizing RNA Modifications in Single Neurons Using Mass Spectrometry
Published on: April 21, 2022
METTL1-mediated N7-methylguanosine epitranscriptomic alterations modulate mRNA stability of neurodegenerative
Jianping Tang1, Yapeng Ren2, Jingwen Li1
1Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujia 350001, China.
Abstract:
Excessive cobalt exposure adversely affects the nervous system, yet the underlying neurotoxic mechanisms remain largely elusive. In the present study, using human neuroblastoma H4 cells exposed to cobalt chloride (CoCl₂) as an in vitro model, we demonstrate for the first time that CoCl₂ induces widespread alterations in m7G modification in genes associated with neurodegenerative disease. MeRIP-sequencing (MeRIP-seq) analysis revealed significant remodeling of m7G modification features, including sequence motifs, genomic distribution, and peak densities following CoCl₂ exposure. Differentially methylated genes were enriched in pathways governing nervous system function, neurotransmitter transport, neuronal projection guidance, axonogenesis, and axonal guidance. Integration of MeRIP-seq and RNA-seq data further demonstrated that CoCl₂ concurrently induced differential m7G methylation and expression of genes implicated in central nervous system function and neurodegenerative disease pathways. Mechanistically, CoCl₂ suppressed m7G modification levels by downregulating the methyltransferase complex components methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4). More importantly, METTL1 overexpression attenuated CoCl₂-induced downregulation of neurodegenerative disease-associated genes runt-related transcription factor 2 (RUNX2), repulsive guidance molecule A (RGMA), and unc-5 netrin receptor C (UNC5C) by modulating mRNA decay. Moreover, MeRIP-qPCR further confirmed that cobalt exposure significantly reduced m7G modification on these transcripts, and this reduction was restored by METTL1 overexpression, thereby supporting a regulatory role of m7G modification in target mRNA expression. These findings establish a pivotal role for m7G modification in environmental neurotoxicant-induced neurodegeneration and reveal cobalt-related RNA regulatory paradigm that expands our understanding of heavy metal-driven epitranscriptomic dysregulation, and hence offering novel therapeutic targets.
Insights
Cobalt exposure alters m7G RNA modifications in neurodegenerative disease genes. METTL1 (methyltransferase-like 1) overexpression can restore these modifications and gene expression, suggesting a new therapeutic target for heavy metal neurotoxicity.
Area of Science:
- Neuroscience
- Molecular Biology
- Toxicology
Background:
- Excessive cobalt exposure is known to harm the nervous system, but the specific neurotoxic mechanisms are not well understood.
- Investigating the role of RNA modifications in cobalt-induced neurotoxicity is crucial for understanding these mechanisms.
Purpose of the Study:
- To investigate the impact of cobalt chloride (CoCl₂) on m7G RNA modifications in human neuroblastoma cells.
- To identify genes and pathways affected by CoCl₂-induced epitranscriptomic changes.
- To elucidate the role of methyltransferase-like 1 (METTL1) in mediating cobalt's neurotoxic effects on RNA regulation.
Main Methods:
- Utilized human neuroblastoma H4 cells as an in vitro model for cobalt exposure.
- Performed methylated RNA immunoprecipitation followed by sequencing (MeRIP-seq) to analyze m7G modification patterns.
- Integrated MeRIP-seq and RNA-sequencing (RNA-seq) data to assess gene expression and methylation changes concurrently.
- Employed MeRIP-quantitative PCR (MeRIP-qPCR) to validate specific m7G modification alterations.
Main Results:
- CoCl₂ exposure induced significant alterations in m7G modification across genes linked to neurodegenerative diseases and nervous system function.
- Differentially methylated genes were enriched in pathways critical for neuronal development and neurotransmitter transport.
- Cobalt suppressed m7G levels by downregulating METTL1 and WDR4, key components of the methyltransferase complex.
- METTL1 overexpression counteracted CoCl₂-induced downregulation of neurodegenerative genes (RUNX2, RGMA, UNC5C) by modulating mRNA decay.
Conclusions:
- m7G RNA modification plays a critical role in cobalt-induced neurotoxicity.
- Cobalt exposure dysregulates epitranscriptomics, impacting genes involved in neurodegeneration.
- METTL1-mediated m7G modification represents a potential therapeutic target for heavy metal-induced neurotoxicity.
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