Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model

Ko Omura, Takeki Uehara, Yuji Morikawa, Hitomi Hayashi, Kunitoshi Mitsumori, Keiichi Minami, Masayuki Kanki, Hiroshi Yamada, Atsushi Ono, Tetsuro Urushidani

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Recent studies have shown that epigenetic alterations correlate with carcinogenesis in various tissues. Identification of these alterations might help characterize the early stages of carcinogenesis. We comprehensively analyzed DNA methylation and gene expression in livers obtained from rats exposed to nitrosodiethylamine (DEN) followed by a promoter of hepatic carcinogenesis, phenobarbital (PB). The combination of DEN and PB induced marked increases in number and area of glutathione S-transferase-placental form (GST-P)-positive foci in the liver. In the liver of rats that received 30 mg/kg of DEN, pathway analysis revealed alterations of common genes in terms of gene expression and DNA methylation, and that these alterations were related to immune responses. Hierarchical clustering analysis of the expression of common genes from public data obtained through the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) showed that carcinogenic compounds clustered together. MBD-seq and GeneChip analysis indicated that major histocompatibility complex class Ib gene RT1-CE5, which has an important role in antigen presentation, was hypomethylated around the promoter region and specifically induced in the livers of DEN-treated rats. Further, immunohistochemical analysis indicated that the co-localization of GST-P and protein homologous to RT1-CE5 was present at the foci of some regions. These results suggest that common genes were altered in terms of both DNA methylation and expression in livers, with preneoplastic foci indicating carcinogenic potential, and that immune responses are involved in early carcinogenesis. In conclusion, the present study identified a specific profile of DNA methylation and gene expression in livers with preneoplastic foci. Early epigenetic perturbations of immune responses might correlate with the early stages of hepatocarcinogenesis.

Original languageEnglish
Pages (from-to)837-848
Number of pages12
JournalJournal of Toxicological Sciences
Volume39
Issue number6
DOIs
Publication statusPublished - Dec 1 2014
Externally publishedYes

Fingerprint

DNA Methylation
Gene expression
Liver
Rats
Gene Expression
Genes
Carcinogenesis
Phenobarbital
Glutathione Transferase
Epigenomics
Diethylnitrosamine
Toxicogenetics
Pregnancy Proteins
Genetic Promoter Regions
Antigen Presentation
Toxicity
Genomics
Major Histocompatibility Complex
Cluster Analysis
Tissue

Keywords

  • Altered hepatocellular foci
  • Carcinogenesis
  • DNA methylation
  • GST-P
  • Liver

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

Omura, K., Uehara, T., Morikawa, Y., Hayashi, H., Mitsumori, K., Minami, K., ... Urushidani, T. (2014). Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model. Journal of Toxicological Sciences, 39(6), 837-848. https://doi.org/10.2131/jts.39.837

Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model. / Omura, Ko; Uehara, Takeki; Morikawa, Yuji; Hayashi, Hitomi; Mitsumori, Kunitoshi; Minami, Keiichi; Kanki, Masayuki; Yamada, Hiroshi; Ono, Atsushi; Urushidani, Tetsuro.

In: Journal of Toxicological Sciences, Vol. 39, No. 6, 01.12.2014, p. 837-848.

Research output: Contribution to journalArticle

Omura, K, Uehara, T, Morikawa, Y, Hayashi, H, Mitsumori, K, Minami, K, Kanki, M, Yamada, H, Ono, A & Urushidani, T 2014, 'Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model', Journal of Toxicological Sciences, vol. 39, no. 6, pp. 837-848. https://doi.org/10.2131/jts.39.837
Omura, Ko ; Uehara, Takeki ; Morikawa, Yuji ; Hayashi, Hitomi ; Mitsumori, Kunitoshi ; Minami, Keiichi ; Kanki, Masayuki ; Yamada, Hiroshi ; Ono, Atsushi ; Urushidani, Tetsuro. / Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model. In: Journal of Toxicological Sciences. 2014 ; Vol. 39, No. 6. pp. 837-848.
@article{3f7f10d0644c4c2098d43532db64610f,
title = "Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model",
abstract = "Recent studies have shown that epigenetic alterations correlate with carcinogenesis in various tissues. Identification of these alterations might help characterize the early stages of carcinogenesis. We comprehensively analyzed DNA methylation and gene expression in livers obtained from rats exposed to nitrosodiethylamine (DEN) followed by a promoter of hepatic carcinogenesis, phenobarbital (PB). The combination of DEN and PB induced marked increases in number and area of glutathione S-transferase-placental form (GST-P)-positive foci in the liver. In the liver of rats that received 30 mg/kg of DEN, pathway analysis revealed alterations of common genes in terms of gene expression and DNA methylation, and that these alterations were related to immune responses. Hierarchical clustering analysis of the expression of common genes from public data obtained through the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) showed that carcinogenic compounds clustered together. MBD-seq and GeneChip analysis indicated that major histocompatibility complex class Ib gene RT1-CE5, which has an important role in antigen presentation, was hypomethylated around the promoter region and specifically induced in the livers of DEN-treated rats. Further, immunohistochemical analysis indicated that the co-localization of GST-P and protein homologous to RT1-CE5 was present at the foci of some regions. These results suggest that common genes were altered in terms of both DNA methylation and expression in livers, with preneoplastic foci indicating carcinogenic potential, and that immune responses are involved in early carcinogenesis. In conclusion, the present study identified a specific profile of DNA methylation and gene expression in livers with preneoplastic foci. Early epigenetic perturbations of immune responses might correlate with the early stages of hepatocarcinogenesis.",
keywords = "Altered hepatocellular foci, Carcinogenesis, DNA methylation, GST-P, Liver",
author = "Ko Omura and Takeki Uehara and Yuji Morikawa and Hitomi Hayashi and Kunitoshi Mitsumori and Keiichi Minami and Masayuki Kanki and Hiroshi Yamada and Atsushi Ono and Tetsuro Urushidani",
year = "2014",
month = "12",
day = "1",
doi = "10.2131/jts.39.837",
language = "English",
volume = "39",
pages = "837--848",
journal = "Journal of Toxicological Sciences",
issn = "0388-1350",
publisher = "Japanese Society of Toxicological Sciences",
number = "6",

}

TY - JOUR

T1 - Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model

AU - Omura, Ko

AU - Uehara, Takeki

AU - Morikawa, Yuji

AU - Hayashi, Hitomi

AU - Mitsumori, Kunitoshi

AU - Minami, Keiichi

AU - Kanki, Masayuki

AU - Yamada, Hiroshi

AU - Ono, Atsushi

AU - Urushidani, Tetsuro

PY - 2014/12/1

Y1 - 2014/12/1

N2 - Recent studies have shown that epigenetic alterations correlate with carcinogenesis in various tissues. Identification of these alterations might help characterize the early stages of carcinogenesis. We comprehensively analyzed DNA methylation and gene expression in livers obtained from rats exposed to nitrosodiethylamine (DEN) followed by a promoter of hepatic carcinogenesis, phenobarbital (PB). The combination of DEN and PB induced marked increases in number and area of glutathione S-transferase-placental form (GST-P)-positive foci in the liver. In the liver of rats that received 30 mg/kg of DEN, pathway analysis revealed alterations of common genes in terms of gene expression and DNA methylation, and that these alterations were related to immune responses. Hierarchical clustering analysis of the expression of common genes from public data obtained through the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) showed that carcinogenic compounds clustered together. MBD-seq and GeneChip analysis indicated that major histocompatibility complex class Ib gene RT1-CE5, which has an important role in antigen presentation, was hypomethylated around the promoter region and specifically induced in the livers of DEN-treated rats. Further, immunohistochemical analysis indicated that the co-localization of GST-P and protein homologous to RT1-CE5 was present at the foci of some regions. These results suggest that common genes were altered in terms of both DNA methylation and expression in livers, with preneoplastic foci indicating carcinogenic potential, and that immune responses are involved in early carcinogenesis. In conclusion, the present study identified a specific profile of DNA methylation and gene expression in livers with preneoplastic foci. Early epigenetic perturbations of immune responses might correlate with the early stages of hepatocarcinogenesis.

AB - Recent studies have shown that epigenetic alterations correlate with carcinogenesis in various tissues. Identification of these alterations might help characterize the early stages of carcinogenesis. We comprehensively analyzed DNA methylation and gene expression in livers obtained from rats exposed to nitrosodiethylamine (DEN) followed by a promoter of hepatic carcinogenesis, phenobarbital (PB). The combination of DEN and PB induced marked increases in number and area of glutathione S-transferase-placental form (GST-P)-positive foci in the liver. In the liver of rats that received 30 mg/kg of DEN, pathway analysis revealed alterations of common genes in terms of gene expression and DNA methylation, and that these alterations were related to immune responses. Hierarchical clustering analysis of the expression of common genes from public data obtained through the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) showed that carcinogenic compounds clustered together. MBD-seq and GeneChip analysis indicated that major histocompatibility complex class Ib gene RT1-CE5, which has an important role in antigen presentation, was hypomethylated around the promoter region and specifically induced in the livers of DEN-treated rats. Further, immunohistochemical analysis indicated that the co-localization of GST-P and protein homologous to RT1-CE5 was present at the foci of some regions. These results suggest that common genes were altered in terms of both DNA methylation and expression in livers, with preneoplastic foci indicating carcinogenic potential, and that immune responses are involved in early carcinogenesis. In conclusion, the present study identified a specific profile of DNA methylation and gene expression in livers with preneoplastic foci. Early epigenetic perturbations of immune responses might correlate with the early stages of hepatocarcinogenesis.

KW - Altered hepatocellular foci

KW - Carcinogenesis

KW - DNA methylation

KW - GST-P

KW - Liver

UR - http://www.scopus.com/inward/record.url?scp=84908507872&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908507872&partnerID=8YFLogxK

U2 - 10.2131/jts.39.837

DO - 10.2131/jts.39.837

M3 - Article

VL - 39

SP - 837

EP - 848

JO - Journal of Toxicological Sciences

JF - Journal of Toxicological Sciences

SN - 0388-1350

IS - 6

ER -