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Abstract
It was recently shown that a large portion of the human transcriptome can originate from within repetitive elements, leading to ectopic expression of protein-coding genes. However the mechanism of transcriptional activation of repetitive elements has not been definitively elucidated. For the first time, we directly demonstrate that hypomethylation of retrotransposons can cause altered gene expression in humans. We also reveal that active LINE-1s switch from a tetranucleosome to dinucleosome structure, acquiring H2A.Z- and nucleosome-free regions upstream of TSSs, previously shown only at active single-copy genes. Hypomethylation of a specific LINE-1 promoter was also found to induce an alternate transcript of the MET oncogene in bladder tumors and across the entire urothelium of tumor-bearing bladders. These data show that, in addition to contributing to chromosomal instability, hypomethylation of LINE-1s can alter the functional transcriptome and plays a role not only in human disease but also in disease predisposition.
Highlights
Aberrant DNA methylation is involved in the initiation and progression of carcinogenesis and includes both hypermethylation of CpG islands at gene promoters and global hypomethylation
We directly demonstrate for the first time the causal relationship between DNA hypomethylation and transcriptional activation of LINE-1 promoters
For the first time to our knowledge, we have elucidated the role of epigenetics in the transcriptional activity of L1s by utilizing novel assays capable of examining the methylation status and chromatin structure of specific L1s and expression of alternate transcripts originating from the L1 promoters
Summary
Aberrant DNA methylation is involved in the initiation and progression of carcinogenesis and includes both hypermethylation of CpG islands at gene promoters and global hypomethylation. While a small portion of hypomethylation occurs at gene promoters, resulting in overexpression of certain oncogenes [1,2], the majority occurs at repetitive elements, such as long interspersed nuclear elements (LINE-1s or L1s) [3]. In mice hypomethylation of transposable elements can lead to disruption of normal gene function [6]. While it is well known that repetitive elements are hypomethylated in cancer, it has never been directly demonstrated that hypomethylation of a retrotransposon leads to ectopic gene expression in humans
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