Abstract
In human cancers, the methylation of long interspersed nuclear element -1 (LINE-1 or L1) retrotransposons is reduced. This occurs within the context of genome wide hypomethylation, and although it is common, its role is poorly understood. L1s are widely distributed both inside and outside of genes, intragenic and intergenic, respectively. Interestingly, the insertion of active full-length L1 sequences into host gene introns disrupts gene expression. Here, we evaluated if intragenic L1 hypomethylation influences their host gene expression in cancer. First, we extracted data from L1base (http://l1base.molgen.mpg.de), a database containing putatively active L1 insertions, and compared intragenic and intergenic L1 characters. We found that intragenic L1 sequences have been conserved across evolutionary time with respect to transcriptional activity and CpG dinucleotide sites for mammalian DNA methylation. Then, we compared regulated mRNA levels of cells from two different experiments available from Gene Expression Omnibus (GEO), a database repository of high throughput gene expression data, (http://www.ncbi.nlm.nih.gov/geo) by chi-square. The odds ratio of down-regulated genes between demethylated normal bronchial epithelium and lung cancer was high (p<1E−27; OR = 3.14; 95% CI = 2.54–3.88), suggesting cancer genome wide hypomethylation down-regulating gene expression. Comprehensive analysis between L1 locations and gene expression showed that expression of genes containing L1s had a significantly higher likelihood to be repressed in cancer and hypomethylated normal cells. In contrast, many mRNAs derived from genes containing L1s are elevated in Argonaute 2 (AGO2 or EIF2C2)-depleted cells. Hypomethylated L1s increase L1 mRNA levels. Finally, we found that AGO2 targets intronic L1 pre-mRNA complexes and represses cancer genes. These findings represent one of the mechanisms of cancer genome wide hypomethylation altering gene expression. Hypomethylated intragenic L1s are a nuclear siRNA mediated cis-regulatory element that can repress genes. This epigenetic regulation of retrotransposons likely influences many aspects of genomic biology.
Highlights
In cancer, DNA methylation in the rest of the genome, at a long interspersed nuclear element-1 (LINE-1 or L1) retrotransposon, is generally depleted and this event occurs within the context of genome wide or global hypomethylation [1,2,3]
Statistical analysis revealed that there are numerous structural characteristics of intragenic L1s that are distinct from intergenic L1s (Fig. 1 and Supporting Table S2). 100 chi-square tests analyzed variations of the sequences that determine L1 transcriptional and retrotranspositional activity and the presence of CpG islands and 57 of the tests were significantly different at p values,0.001 (Fig. 1D and Supporting Table S2)
We further evaluated an mRNA microarray experiment hybridized by AGO2 precipitated RNA [48] and found that AGO2 may not directly degrade mRNAs that are derived from genes containing L1s
Summary
DNA methylation in the rest of the genome, at a long interspersed nuclear element-1 (LINE-1 or L1) retrotransposon, is generally depleted and this event occurs within the context of genome wide or global hypomethylation [1,2,3]. The role of global L1 methylation, on genome wide gene expression, is less frequently studied and not well-characterized. The effects of promoter methylation on chromatin configuration and gene transcription have been well-documented [8]. Unique methylated sequences in introns are frequently found in highly expressed genes [9]. The formation of heterochromatin by dense intragenic DNA methylation limits the efficiency of RNA polymerase [10]. These evidences implied that methylation of intragenic repetitive sequences, including L1s, may be important for maintaining the normal function of linked genomic loci
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