Polychlorinated biphenyls alter hepatic m6A mRNA methylation in a mouse model of environmental liver disease.

Autor: Petri BJ; Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA., Piell KM; Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA., Wahlang B; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA., Head KZ; University of Louisville Hepatobiology and Toxicology Center, USA., Andreeva K; KY INBRE Bioinformatics Core, University of Louisville, USA; Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, 94304, USA., Rouchka EC; Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA; KY INBRE Bioinformatics Core, University of Louisville, USA., Cave MC; Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA., Klinge CM; Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA. Electronic address: carolyn.klinge@louisville.edu.
Jazyk: angličtina
Zdroj: Environmental research [Environ Res] 2023 Jan 01; Vol. 216 (Pt 3), pp. 114686. Date of Electronic Publication: 2022 Oct 28.
DOI: 10.1016/j.envres.2022.114686
Abstrakt: Exposure to polychlorinated biphenyls (PCBs) has been associated with liver injury in human cohorts and with nonalcoholic steatohepatitis (NASH) in mice fed a high fat diet (HFD). N (6)-methyladenosine (m6A) modification of mRNA regulates transcript fate, but the contribution of m6A modification on the regulation of transcripts in PCB-induced steatosis and fibrosis is unknown. This study tested the hypothesis that PCB and HFD exposure alters the levels of m6A modification in transcripts that play a role in NASH in vivo. Male C57Bl6/J mice were fed a HFD (12 wks) and administered a single oral dose of Aroclor1260, PCB126, or Aroclor1260 + PCB126. Genome-wide identification of m6A peaks was accomplished by m6A mRNA immunoprecipitation sequencing (m6A-RIP) and the mRNA transcriptome identified by RNA-seq. Exposure of HFD-fed mice to Aroclor1260 decreased the number of m6A peaks and m6A-containing genes relative to PCB vehicle control whereas PCB126 or the combination of Aroclor1260 + PCB126 increased m6A modification frequency. ∼41% of genes had one m6A peak and ∼49% had 2-4 m6A peaks. 117 m6A peaks were common in the four experimental groups. The Aroclor1260 + PCB126 exposure group showed the highest number (52) of m6A-peaks. qRT-PCR confirmed enrichment of m6A-containing fragments of the Apob transcript with PCB exposure. A1cf transcript abundance, m6A peak count, and protein abundance was increased with Aroclor1260 + PCB126 co-exposure. Irrespective of the PCB type, all PCB groups exhibited enriched pathways related to lipid/lipoprotein metabolism and inflammation through the m6A modification. Integrated analysis of m6A-RIP-seq and mRNA-seq identified 242 differentially expressed genes (DEGs) with increased or reduced number of m6A peaks. These data show that PCB exposure in HFD-fed mice alters the m6A landscape offering an additional layer of regulation of gene expression affecting a subset of gene responses in NASH.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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