6 research outputs found
Hypomethylation of Intragenic LINE-1 Represses Transcription in Cancer Cells through AGO2
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