Dysregulation of DNA methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells

Fabio Caradonna, Maurizio Mauro, Catherine B. Klein, Maurizio Mauro

Risultato della ricerca: Article

16 Citazioni (Scopus)

Abstract

The mechanisms by which arsenic-induced genomic instability is initiated and maintained are poorly understood. To investigate potential epigenetic mechanisms, in this study we evaluated global DNA methylation levels in V79 cells and human HaCaT keratinocytes at several time points during expanded growth of cell cultures following removal of arsenite exposures. We have found altered genomic methylation patterns that persisted up to 40 cell generations in HaCaT cells after the treatments were withdrawn. Moreover, mRNA expression levels were evaluated by RT-PCR for DNMT1, DNMT3A, DNMT3B, HMLH1, and HMSH2 genes, demonstrating that the down regulation of DNMT3A and DNMT3B genes, but not DNMT1, occurred in an arsenic dose-dependent manner, and persisted for many cell generations following removal of the arsenite, offering a plausible mechanism of persistently genotoxic arsenic action. Analyses of promoter methylation status of the DNA mismatch repair genes HMLH1 and HMSH2 show that HMSH2, but not HMLH1, was epigenetically regulated by promoter hypermethylation changes following arsenic treatment. The results reported here demonstrate that arsenic exposure promptly induces genome-wide global DNA hypomethylation, and some specific gene promoter methylation changes, that persist for many cell generations following withdrawal of arsenite, supporting the hypothesis that the cells undergo epigenetic reprogramming at both the gene and genome level that is durable over many cell generations in the absence of further arsenic treatment. These DNA methylation changes, in concert with other known epigenome alterations, are likely contributing to long-lasting arsenic-induced genomic instability that manifests in several ways, including aberrant chromosomal effects. Environ. Mol. Mutagen., 2015. © 2015 Wiley Periodicals, Inc.
Lingua originaleEnglish
pagine (da-a)137-150
Numero di pagine14
RivistaDefault journal
Volume57
Stato di pubblicazionePublished - 2015

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Genomic Instability
Arsenic
DNA Methylation
Methylation
Genes
Epigenomics
Genome
DNA Mismatch Repair
Mutagens
Keratinocytes
Down-Regulation
Cell Culture Techniques
Polymerase Chain Reaction
Messenger RNA
DNA
Growth
arsenite

All Science Journal Classification (ASJC) codes

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

Cita questo

Dysregulation of DNA methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells. / Caradonna, Fabio; Mauro, Maurizio; Klein, Catherine B.; Mauro, Maurizio.

In: Default journal, Vol. 57, 2015, pag. 137-150.

Risultato della ricerca: Article

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abstract = "The mechanisms by which arsenic-induced genomic instability is initiated and maintained are poorly understood. To investigate potential epigenetic mechanisms, in this study we evaluated global DNA methylation levels in V79 cells and human HaCaT keratinocytes at several time points during expanded growth of cell cultures following removal of arsenite exposures. We have found altered genomic methylation patterns that persisted up to 40 cell generations in HaCaT cells after the treatments were withdrawn. Moreover, mRNA expression levels were evaluated by RT-PCR for DNMT1, DNMT3A, DNMT3B, HMLH1, and HMSH2 genes, demonstrating that the down regulation of DNMT3A and DNMT3B genes, but not DNMT1, occurred in an arsenic dose-dependent manner, and persisted for many cell generations following removal of the arsenite, offering a plausible mechanism of persistently genotoxic arsenic action. Analyses of promoter methylation status of the DNA mismatch repair genes HMLH1 and HMSH2 show that HMSH2, but not HMLH1, was epigenetically regulated by promoter hypermethylation changes following arsenic treatment. The results reported here demonstrate that arsenic exposure promptly induces genome-wide global DNA hypomethylation, and some specific gene promoter methylation changes, that persist for many cell generations following withdrawal of arsenite, supporting the hypothesis that the cells undergo epigenetic reprogramming at both the gene and genome level that is durable over many cell generations in the absence of further arsenic treatment. These DNA methylation changes, in concert with other known epigenome alterations, are likely contributing to long-lasting arsenic-induced genomic instability that manifests in several ways, including aberrant chromosomal effects. Environ. Mol. Mutagen., 2015. {\circledC} 2015 Wiley Periodicals, Inc.",
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