LINE-1 Hypomethylation in a Choline-Deficiency-Induced  Liver Cancer in Rats: Dependence on Feeding Period

Asada, Kiyoshi; Kotake, Yashige; Asada, Rumiko; Saunders, Deborah; Broyles, Robert H.; Towner, Rheal A.; Fukui, Hiroshi; Floyd, Robert A.

doi:https://doi.org/10.1155/JBB/2006/17142

BioMed Research International

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LINE-1 Retrotransposition: Impact on Genome Stability and Diversity and Human Disease

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Research Article | Open Access

Volume 2006 | Article ID 017142 | https://doi.org/10.1155/JBB/2006/17142

LINE-1 Hypomethylation in a Choline-Deficiency-Induced Liver Cancer in Rats: Dependence on Feeding Period

Kiyoshi Asada,^1,2Yashige Kotake,¹Rumiko Asada,¹Deborah Saunders,¹Robert H. Broyles,^1,3Rheal A. Towner,¹Hiroshi Fukui,¹and Robert A. Floyd^1,3

Received08 Jun 2005

Revised28 Nov 2005

Accepted04 Dec 2005

Published06 Mar 2006

Abstract

Chronic feeding of methyl-donor (methionine, choline, folic acid, and vitamin B12) deficient diet induces hepatocellular carcinoma formation in rats. Previous studies have shown that promoter CpG islands in various cancer-related genes are aberrantly methylated in this model. Moreover, the global genome in methyl-donor-deficient diet fed rats contains a lesser amount of 5-methylcytosine than control livers. It is speculated that more than 90% of all 5-methylcytosines lie within the CpG islands of the transposons, including the long/short interspersed nucleotide elements (LINE and SINE). It is considered that the 5-methylcytosines in LINE-1 limit the ability of retrotransposons to be activated and transcribed; therefore, the extent of hypomethylation of LINE-1 could be a surrogate marker for aberrant methylation in other tumor-related genes as well as genome instability. Additionally, LINE-1 methylation status has been shown to be a good indicator of genome-wide methylation. In this study, we determined cytosine methylation status in the LINE-1 repetitive sequences of rats fed a choline-deficient (CD) diet for various durations and compared these with rats fed a choline-sufficient (CS) diet. The methylation status of LINE-1 was assessed by the combined bisulfite restriction analysis (COBRA) method, where the amount of bisulfite-modified and RsaI-cleaved DNA was quantified using gel electrophoresis. Progressive hypomethylation was observed in LINE-1 of CD livers as a function of feeding time; that is, the amount of cytosine in total cytosine (methylated and unmethylated) increased from 11.1% (1 week) to 19.3% (56 weeks), whereas in the control CS livers, it increased from 9.2% to 12.9%. Hypomethylation in tumor tissues was slightly higher (6%) than the nontumorous surrounding tissue. The present result also indicates that age is a factor influencing the extent of cytosine methylation.

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Copyright © 2006 Kiyoshi Asada et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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