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Title: Stable loss of global DNA methylation in the radiation-target tissue-A possible mechanism contributing to radiation carcinogenesis?

Abstract

Radiation-induced lymphomagenesis and leukemogenesis are complex processes involving both genetic and epigenetic changes. Although genetic alterations during radiation-induced lymphoma- and leukemogenesis are fairly well studied, the role of epigenetic changes has been largely overlooked. Rodent models are valuable tools for identifying molecular mechanisms of lymphoma and leukemogenesis. A widely used mouse model of radiation-induced thymic lymphoma is characterized by a lengthy 'pre-lymphoma' period. Delineating molecular changes occurring during the pre-lymphoma period is crucial for understanding the mechanisms of radiation-induced leukemia/lymphoma development. In the present study, we investigated the role of radiation-induced DNA methylation changes in the radiation carcinogenesis target organ-thymus, and non-target organ-muscle. This study is the first report on the radiation-induced epigenetic changes in radiation-target murine thymus during the pre-lymphoma period. We have demonstrated that acute and fractionated whole-body irradiation significantly altered DNA methylation pattern in murine thymus leading to a massive loss of global DNA methylation. We have also observed that irradiation led to increased levels of DNA strand breaks 6 h following the initial exposure. The majority of radiation-induced DNA strand breaks were repaired 1 month after exposure. DNA methylation changes, though, were persistent and significant radiation-induced DNA hypomethylation was observed in thymus 1 month after exposure.more » In sharp contrast to thymus, no significant persistent changes were noted in the non-target muscle tissue. The presence of stable DNA hypomethylation in the radiation-target tissue, even though DNA damage resulting from initial genotoxic radiation insult was repaired, suggests of the importance of epigenetic mechanisms in the development of radiation-related pathologies. The possible role of radiation-induced DNA hypomethylation in radiation-induced genome instability and aberrant gene expression in molecular etiology of thymic lymphomas is discussed.« less

Authors:
 [1];  [2];  [3]
  1. Department of Biological Sciences, University of Lethbridge, 4401 University Drive, Lethbridge, Alta., T1K 3M4 (Canada)
  2. Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States)
  3. Department of Biological Sciences, University of Lethbridge, 4401 University Drive, Lethbridge, Alta., T1K 3M4 (Canada). E-mail: olga.kovalchuk@uleth.ca
Publication Date:
OSTI Identifier:
20713443
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 337; Journal Issue: 2; Other Information: DOI: 10.1016/j.bbrc.2005.09.084; PII: S0006-291X(05)02049-8; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; BIOLOGICAL RADIATION EFFECTS; DNA; ETIOLOGY; GENES; LEUKEMIA; LEUKEMOGENESIS; LYMPHOMAS; METHYLATION; MICE; MUSCLES; STRAND BREAKS; THYMUS; WHOLE-BODY IRRADIATION

Citation Formats

Koturbash, Igor, Pogribny, Igor, and Kovalchuk, Olga. Stable loss of global DNA methylation in the radiation-target tissue-A possible mechanism contributing to radiation carcinogenesis?. United States: N. p., 2005. Web. doi:10.1016/j.bbrc.2005.09.084.
Koturbash, Igor, Pogribny, Igor, & Kovalchuk, Olga. Stable loss of global DNA methylation in the radiation-target tissue-A possible mechanism contributing to radiation carcinogenesis?. United States. doi:10.1016/j.bbrc.2005.09.084.
Koturbash, Igor, Pogribny, Igor, and Kovalchuk, Olga. Fri . "Stable loss of global DNA methylation in the radiation-target tissue-A possible mechanism contributing to radiation carcinogenesis?". United States. doi:10.1016/j.bbrc.2005.09.084.
@article{osti_20713443,
title = {Stable loss of global DNA methylation in the radiation-target tissue-A possible mechanism contributing to radiation carcinogenesis?},
author = {Koturbash, Igor and Pogribny, Igor and Kovalchuk, Olga},
abstractNote = {Radiation-induced lymphomagenesis and leukemogenesis are complex processes involving both genetic and epigenetic changes. Although genetic alterations during radiation-induced lymphoma- and leukemogenesis are fairly well studied, the role of epigenetic changes has been largely overlooked. Rodent models are valuable tools for identifying molecular mechanisms of lymphoma and leukemogenesis. A widely used mouse model of radiation-induced thymic lymphoma is characterized by a lengthy 'pre-lymphoma' period. Delineating molecular changes occurring during the pre-lymphoma period is crucial for understanding the mechanisms of radiation-induced leukemia/lymphoma development. In the present study, we investigated the role of radiation-induced DNA methylation changes in the radiation carcinogenesis target organ-thymus, and non-target organ-muscle. This study is the first report on the radiation-induced epigenetic changes in radiation-target murine thymus during the pre-lymphoma period. We have demonstrated that acute and fractionated whole-body irradiation significantly altered DNA methylation pattern in murine thymus leading to a massive loss of global DNA methylation. We have also observed that irradiation led to increased levels of DNA strand breaks 6 h following the initial exposure. The majority of radiation-induced DNA strand breaks were repaired 1 month after exposure. DNA methylation changes, though, were persistent and significant radiation-induced DNA hypomethylation was observed in thymus 1 month after exposure. In sharp contrast to thymus, no significant persistent changes were noted in the non-target muscle tissue. The presence of stable DNA hypomethylation in the radiation-target tissue, even though DNA damage resulting from initial genotoxic radiation insult was repaired, suggests of the importance of epigenetic mechanisms in the development of radiation-related pathologies. The possible role of radiation-induced DNA hypomethylation in radiation-induced genome instability and aberrant gene expression in molecular etiology of thymic lymphomas is discussed.},
doi = {10.1016/j.bbrc.2005.09.084},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 337,
place = {United States},
year = {Fri Nov 18 00:00:00 EST 2005},
month = {Fri Nov 18 00:00:00 EST 2005}
}
  • Sizes of C-band heterochromatin regions were estimated in embryonic and extraembryonic lineages. These regions in chromosomes 1 and 16, containing mainly satellite 2 DNA, were significantly longer in extraembryonic tissues than in embryonic tissues. The differences in length between chromosome 9 C-band heterochromatin, which contained satellite 3 DNA, and Y chromosome C-band heterochromatin, which contained all four classical satellite types, were not significant between the two tissues. Our data, together with other findings on the correlation between chromosome compactization and DNA methylation, indicated that the observed variations in C-band length reflected a tissue-specific pattern of heterochromatin methylation. Satellite 2 DNAmore » probably was the most sensitive target for the decondensation effect of DNA methylation compared with other satellite types. 24 refs., 1 tab.« less
  • No abstract prepared.
  • To evaluate the significance of alterations in cell adhesion-related genes methylation during lung multistep carcinogenesis induced by the genotoxic carcinogens 3-methylcholanthrene (MCA) and diethylnitrosamine (DEN), tissue samples microdissected from MCA/DEN-induced rat lung carcinogenesis model were subjected to methylation-specific PCR to evaluate the DNA methylation status of CADM1, TIMP3, E-cadherin and N-cadherin. Immunohistochemistry was used to determine protein expression of CADM1, TIMP3, N-cadherin and the DNA methyltransferases (DNMTs) 1, 3a and 3b. E-cadherin hypermethylation was not detected in any tissue. CADM1, TIMP3 and N-cadherin hypermethylation was correlated with the loss of their protein expression during the progression of pathologic lesions. Themore » prevalence of DNA methylation of at least one gene and the average number of methylated genes increased with the histological progression. DNMT1 and DNMT3a protein expression increased progressively during the stages of lung carcinogenesis, whereas DNMT3b overexpression was only found in several samples. Furthermore, DNMT1 protein expression levels were correlated with CADM1 methylation, and DNMT3a protein expression levels were correlated with CADM1, TIMP3 and N-cadherin methylation. The average number of methylated genes during carcinogenesis was significantly correlated with DNMT1 and DNMT3a protein expression levels. Moreover, mRNA expression of CADM1 significantly increased after treatment with DNMT inhibitor 5-aza-2'-deoxycytidine in CADM1-methylated primary tumor cell lines. Our findings suggest that an accumulation of hypermethylation accounts for cell adhesion-related gene silencing is associated with dynamic changes in the progression of MCA/DEN-induced rat lung carcinogenesis. We suggest that DNMT1 and DNMT3a protein overexpression may be responsible for this aberrant DNA methylation.« less