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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,...

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Autores principales: Aporntewan, Chatchawit, Phokaew, Chureerat, Piriyapongsa, Jittima, Ngamphiw, Chumpol, Ittiwut, Chupong, Tongsima, Sissades, Mutirangura, Apiwat
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057998/
https://www.ncbi.nlm.nih.gov/pubmed/21423624
http://dx.doi.org/10.1371/journal.pone.0017934
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author Aporntewan, Chatchawit
Phokaew, Chureerat
Piriyapongsa, Jittima
Ngamphiw, Chumpol
Ittiwut, Chupong
Tongsima, Sissades
Mutirangura, Apiwat
author_facet Aporntewan, Chatchawit
Phokaew, Chureerat
Piriyapongsa, Jittima
Ngamphiw, Chumpol
Ittiwut, Chupong
Tongsima, Sissades
Mutirangura, Apiwat
author_sort Aporntewan, Chatchawit
collection PubMed
description 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.
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spelling pubmed-30579982011-03-21 Hypomethylation of Intragenic LINE-1 Represses Transcription in Cancer Cells through AGO2 Aporntewan, Chatchawit Phokaew, Chureerat Piriyapongsa, Jittima Ngamphiw, Chumpol Ittiwut, Chupong Tongsima, Sissades Mutirangura, Apiwat PLoS One Research Article 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. Public Library of Science 2011-03-15 /pmc/articles/PMC3057998/ /pubmed/21423624 http://dx.doi.org/10.1371/journal.pone.0017934 Text en Aporntewan et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Aporntewan, Chatchawit
Phokaew, Chureerat
Piriyapongsa, Jittima
Ngamphiw, Chumpol
Ittiwut, Chupong
Tongsima, Sissades
Mutirangura, Apiwat
Hypomethylation of Intragenic LINE-1 Represses Transcription in Cancer Cells through AGO2
title Hypomethylation of Intragenic LINE-1 Represses Transcription in Cancer Cells through AGO2
title_full Hypomethylation of Intragenic LINE-1 Represses Transcription in Cancer Cells through AGO2
title_fullStr Hypomethylation of Intragenic LINE-1 Represses Transcription in Cancer Cells through AGO2
title_full_unstemmed Hypomethylation of Intragenic LINE-1 Represses Transcription in Cancer Cells through AGO2
title_short Hypomethylation of Intragenic LINE-1 Represses Transcription in Cancer Cells through AGO2
title_sort hypomethylation of intragenic line-1 represses transcription in cancer cells through ago2
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057998/
https://www.ncbi.nlm.nih.gov/pubmed/21423624
http://dx.doi.org/10.1371/journal.pone.0017934
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