METTL1-mediated N7-methylguanosine epitranscriptomic alterations modulate mRNA stability of neurodegenerative disease-associated genes following cobalt exposure.
TL;DR
A pivotal role for m7G modification in environmental neurotoxicant-induced neurodegeneration is established and cobalt-related RNA regulatory paradigm is revealed that expands the understanding of heavy metal-driven epitranscriptomic dysregulation, and hence offering novel therapeutic targets.
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.