Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer

• Published in: PLoS genetics Vol. 6; no. 4; p. e1000917
• Main Authors: Wolff, Erika M, Byun, Hyang-Min, Han, Han F, Sharma, Shikhar, Nichols, Peter W, Siegmund, Kimberly D, Yang, Allen S, Jones, Peter A, Liang, Gangning
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2010; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Bladder cancer; Cell Biology/Gene Expression; Cell Line, Tumor; Chromatin Assembly and Disassembly; Deoxyribonucleic acid; DNA; DNA damage; DNA methylation; DNA Methylation - genetics; Epigenetics; Genetic aspects; Genetics; Genetics and Genomics/Epigenetics; Humans; Long Interspersed Nucleotide Elements - genetics; Medical research; Middle Aged; Molecular Biology/Chromatin Structure; Molecular Biology/DNA Methylation; Molecular Biology/Histone Modification; Oncogenes; Oncology/Bladder Cancer and Urothelial Neoplasias of the Urinary Tract; Physiological aspects; Promoter Regions, Genetic; Promoters (Genetics); Proto-Oncogene Proteins c-met - genetics; Receptors, Growth Factor - genetics; Retrotransposons; Risk factors; Transcriptional Activation; Urinary Bladder Neoplasms - genetics; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1000917

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.