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Transcriptional provirus silencing as a crosstalk of de novo DNA methylation and epigenomic features at the integration site
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SYSNO ASEP 0381590 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Transcriptional provirus silencing as a crosstalk of de novo DNA methylation and epigenomic features at the integration site Author(s) Šenigl, Filip (UMG-J) RID
Auxt, Miroslav (UMG-J)
Hejnar, Jiří (UMG-J) RIDSource Title Nucleic Acids Research. - : Oxford University Press - ISSN 0305-1048
Roč. 40, č. 12 (2012), s. 5298-5312Number of pages 15 s. Language eng - English Country GB - United Kingdom Keywords retrovirus integration ; provirus silencing ; epigenomics Subject RIV EB - Genetics ; Molecular Biology R&D Projects GP301/09/P667 GA ČR - Czech Science Foundation (CSF) GAP502/11/2207 GA ČR - Czech Science Foundation (CSF) CEZ AV0Z50520514 - UMG-J (2005-2011) UT WOS 000305829000019 DOI https://doi.org/10.1093/nar/gks197 Annotation The autonomous transcription of integrated retroviruses strongly depends on genetic and epigenetic effects of the chromatin at the site of integration. These effects are mostly suppressive and proviral activity can be finally silenced by mechanisms, such as DNA methylation and histone modifications. To address the role of the integration site at the whole-genome-scale, we performed clonal analysis of provirus silencing with an avian leucosis/sarcoma virus-based reporter vector and correlated the transcriptional silencing with the epigenomic landscape of respective integrations. We demonstrate efficient provirus silencing in human HCT116 cell line, which is strongly but not absolutely dependent on the de novo DNA methyltransferase activity, particularly of Dnmt3b. Proviruses integrated close to the transcription start sites of active genes into the regions enriched in H3K4 trimethylation display long-term stability of expression and are resistant to the transcriptional silencing after over-expression of Dnmt3a or Dnmt3b. In contrast, proviruses in the intergenic regions tend to spontaneous transcriptional silencing even in Dnmt3a(-/-) Dnmt3b(-/-) cells. The silencing of proviruses within genes is accompanied with DNA methylation of long terminal repeats, whereas silencing in intergenic regions is DNA methylation-independent. These findings indicate that the epigenomic features of integration sites are crucial for their permissivity to the proviral expression. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2013
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