Naturally occurring endo-siRNA silences LINE-1 retrotransposons in human cells through DNA methylation.
Long interspersed nuclear element 1 (LINE-1) retrotransposons are mutagens that are capable of generating deleterious mutations by inserting themselves into genes and affecting gene function in the human genome. In normal cells, the activity of LINE-1 retrotransposon is mostly repressed, maintaining a stable genome structure. In contrast, cancer cells are characterized by aberrant expression of LINE-1 retrotransposons, which, in principle, have the potential to contribute to genomic instability. The mechanistic pathways that regulate LINE-1 expression remain unclear. Using deep-sequencing small RNA analysis, we identified a subset of differentially expressed endo-siRNAs that directly regulate LINE-1 expression. Detailed analyses suggest that these endo-siRNAs are significantly depleted in human breast cancer cells compared with normal breast cells. The overexpression of these endo-siRNAs in cancer cells markedly silences endogenous LINE-1 expression through increased DNA methylation of the LINE-1 5'-UTR promoter. The finding that endo-siRNAs can silence LINE-1 activity through DNA methylation suggests that a functional link exists between the expression of endo-siRNAs and LINE-1 retrotransposons in human cells.
John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
Long
L
Chen
Jane E
JE
Dahlstrom
Sung-Hun
SH
Lee
Danny
D
Rangasamy
D045744:Cell Line, Tumor; D019175:DNA Methylation; D020868:Gene Silencing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D034741:RNA, Small Interfering / Q000378:metabolism*; D017422:Sequence Analysis, DNA
D034741:RNA, Small Interfering