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Epigenomes 2017, 1(3), 24; https://doi.org/10.3390/epigenomes1030024

Large-Scale Integrative Analysis of Epigenetic Modifications Induced by Isotretinoin, Doxycycline and Metronidazole in Murine Colonic Intestinal Epithelial Cells

1
Division of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland
2
Functional Genomics Center Zurich, ETH/University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
3
Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
*
Author to whom correspondence should be addressed.
Academic Editor: Muller Fabbri
Received: 23 October 2017 / Revised: 25 November 2017 / Accepted: 30 November 2017 / Published: 18 December 2017
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Abstract

Environmental factors are playing a central role in triggering inflammatory responses in the intestine. There is increasing evidence that the development of inflammatory bowel disease (IBD) is deriving from an aberrant immune response to the commensal gut microbiota triggered by various environmental factors in a susceptible host. A vitamin A derivate used in acne therapy (isotretinoin) has been inconsistently associated with the onset of IBD. However, what needs to be considered is the previous treatment of acne patients with antibiotics that are also associated with the development of IBD, thus representing a crucial confounding factor. Here, we studied whether doxycycline (acne therapy), metronidazole (IBD therapy) or isotretinoin are able to induce alterations in DNA methylation and microRNA expression patterns in murine colonic intestinal epithelial cells (IECs). Additionally, we analyzed time-dependent changes in the aforementioned epigenetic mechanisms to study how epigenetic signatures evolve over time. As for changes in DNA methylation, we found isotretinoin to have strong demethylating effects, while antibiotic treatment had only a moderate impact. Isotretinoin-mediated demethylation resolved after a washout phase, not supporting an association between isotretinoin treatment and IBD. Regarding microRNA and mRNA expression, isotretinoin and doxycycline, but not metronidazole, potentially induce long-term changes in microRNA/mRNA expression profiles towards the down-regulation of immune responses. Analysis of time-dependent DNA methylation showed stable marks over a time frame of 4 weeks. Furthermore, novel microRNAs were identified (e.g., microRNA-877-3p), which might be of relevance in IEC development. View Full-Text
Keywords: DNA methylation; microRNA expression; intestinal epithelial cells; antibiotics; isotretinoin; IBD DNA methylation; microRNA expression; intestinal epithelial cells; antibiotics; isotretinoin; IBD
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Becker, E.; Bengs, S.; Aluri, S.; Opitz, L.; Atrott, K.; Rost, F.; Leonardi, I.; Stanzel, C.; Raselli, T.; Kasper, S.; Ruiz, P.A.; Rogler, G. Large-Scale Integrative Analysis of Epigenetic Modifications Induced by Isotretinoin, Doxycycline and Metronidazole in Murine Colonic Intestinal Epithelial Cells. Epigenomes 2017, 1, 24.

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