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. 2011 Aug;2(2):315-30.
doi: 10.1007/s13148-011-0032-8. Epub 2011 Apr 10.

Long interspersed nuclear element-1 hypomethylation in cancer: biology and clinical applications

Nakarin Kitkumthorn, Apiwat Mutirangura

Long interspersed nuclear element-1 hypomethylation in cancer: biology and clinical applications

Nakarin Kitkumthorn et al. Clin Epigenetics. 2011 Aug.

Abstract

Epigenetic changes in long interspersed nuclear element-1s (LINE-1s or L1s) occur early during the process of carcinogenesis. A lower methylation level (hypomethylation) of LINE-1 is common in most cancers, and the methylation level is further decreased in more advanced cancers. Consequently, several previous studies have suggested the use of LINE-1 hypomethylation levels in cancer screening, risk assessment, tumor staging, and prognostic prediction. Epigenomic changes are complex, and global hypomethylation influences LINE-1s in a generalized fashion. However, the methylation levels of some loci are dependent on their locations. The consequences of LINE-1 hypomethylation are genomic instability and alteration of gene expression. There are several mechanisms that promote both of these consequences in cis. Therefore, the methylation levels of different sets of LINE-1s may represent certain phenotypes. Furthermore, the methylation levels of specific sets of LINE-1s may indicate carcinogenesis-dependent hypomethylation. LINE-1 methylation pattern analysis can classify LINE-1s into one of three classes based on the number of methylated CpG dinucleotides. These classes include hypermethylation, partial methylation, and hypomethylation. The number of partial and hypermethylated loci, but not hypomethylated LINE-1s, is different among normal cell types. Consequently, the number of hypomethylated loci is a more promising marker than methylation level in the detection of cancer DNA. Further genome-wide studies to measure the methylation level of each LINE-1 locus may improve PCR-based methylation analysis to allow for a more specific and sensitive detection of cancer DNA or for an analysis of certain cancer phenotypes.

Electronic supplementary material: The online version of this article (doi:10.1007/s13148-011-0032-8) contains supplementary material, which is available to authorized users.

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Figures

Fig. 1
Fig. 1
Effect of global hypomethylation in cancer. a Normal genomes contain hypermethylated, partially methylated, and hypomethylated LINE-1s. The methylation levels of each locus are regulated in a location-dependent manner. b The cancer genome contains more hypomethylated LINE-1s. Global hypomethylation decreases the methylation status of many LINE-1 loci. However, there are some loci that are not influenced and some loci that show increased methylation levels. Local mechanisms are also present in cancer cells, and some locations are affected by the process of carcinogenesis
Fig. 2
Fig. 2
LINE-1 can produce two types of unique RNA sequences. One type of unique sequence is the result of LINE-1 RNA transcription proceeding beyond the LINE-1 sequence. The other type occurs when the reverse LINE-1 promoter transcribes unique DNA sequences located beyond the 5′ end of LINE-1
Fig. 3
Fig. 3
Intragenic hypomethylated LINE-1s repress host gene expression via AGO2. The schematic demonstrates that the same gene from three different cells has different levels of intragenic LINE-1 methylation. a Hypermethylated LINE-1. b Partially methylated LINE-1. c Hypomethylated LINE-1. LINE-1 RNA is produced when the methylation of the LINE-1 5′ UTR is reduced. The LINE-1 RNA–pre-mRNA complex is bound by AGO2, and mRNA production is prevented
Fig. 4
Fig. 4
Examples of LINE-1 methylation patterns in three cells. The number of LINE-1 loci and the methylation levels were approximated from the average levels of a previous report (Pobsook et al. 2011). Type I normal cells (a), type II normal cells (b), and cancer cells (c) possess LINE-1 methylation levels of 60.87%, 56.52%, and 44.44%, respectively. Even though different normal cell types contain different methylation levels, the numbers of partially methylated, hypermethylated, and hypomethylated loci were not different. Cancer cells showed lower methylation levels and a lower number of partially methylated loci, but a higher number of hypomethylated LINE-1 loci
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