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

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number115326
JournalEnvironmental Pollution
Volume266
DOIs
StatePublished - Nov 2020

Keywords

  • CoCl
  • Epitranscriptome
  • N-methyladenosine(mA)
  • Neurotoxicity
  • RNA methylation

ASJC Scopus subject areas

  • Toxicology
  • Pollution
  • Health, Toxicology and Mutagenesis

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