Global N6-methyladenosine profiling of cobalt-exposed cortex and human neuroblastoma H4 cells presents epitranscriptomics alterations in neurodegenerative disease-associated genes

Tang, Jianping; Zheng, Chunyan; Zheng, Fuli; Li, Yuqing; Wang, Yuanliang; Aschner, Michael; Guo, Zhenkun; Yu, Guangxia; Wu, Siying; Li, Huangyuan

Global N6-methyladenosine profiling of cobalt-exposed cortex and human neuroblastoma H4 cells presents epitranscriptomics alterations in neurodegenerative disease-associated genes

2020

Excessive exposure to cobalt (Co) is known to make adverse impact on the nervous system, but its detailed mechanisms of neurotoxicity have yet to be determined. In this study, C57BL/6 mice (0, 4, 8, 16 mg/kg CoCl₂, 30 days) and human neuroblastoma H4 cells (0, 100, 400, 600 μM CoCl₂) were used as in vivo and in vitro models. Our results revealed that CoCl₂ intraperitoneal injection caused significant impairments in learning and memory, as well as pathological damage in the nervous system. We further certificated the alteration of m⁶A methylation induced by CoCl₂ exposure. Our findings demonstrate for the first time, significant differences in the degree of m⁶A modification, the biological function of m⁶A-modified transcripts between cortex and H4 cell samples. Specifically, MeRIP-seq and RNA-seq elucidate that CoCl₂ exposure results in differentially m⁶A-modified and expressed genes, which were enriched in pathways involving synaptic transmission, and central nervous system (CNS) development. Mechanistic analyses revealed that CoCl₂ remarkably changed m⁶A modification level by affecting the expression of m⁶A methyltransferase and demethylase, and decreasing the activity of demethylase. We observed variation of m⁶A modification in neurodegenerative disease-associated genes upon CoCl₂ exposure and identified regulatory strategy between m⁶A and potential targets mRNA. Our novel findings provide novel insight into the functional roles of m⁶A modification in neurodegenerative damage caused by environmental neurotoxicants and identify Co-mediated specific RNA regulatory strategy for broadening the epigenetic regulatory mechanism of RNA induced by heavy metals.

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