Identification of microRNA-mRNA functional interactions in UVB-induced senescence of human diploid fibroblasts

BMC Genomics

Research Article

Matthias Hackl¹  Rossella Monteforte¹  Johannes Grillari²  Zlatko Trajanoski³  Edith Hofer³  Pornpimol Charoentong³  Pidder Jansen-Dürr⁴  Michael Neuhaus⁴  Christoph Mueck⁴  Ruth Greussing⁴  Alexander Pauck⁴  Lucia Micutkova⁴  Maria Cavinato⁴  Marcel Scheideler⁵ 

[1] Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190, Vienna, Austria;Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190, Vienna, Austria;Evercyte GmbH, Muthgasse 18, A 1190, Vienna, Austria;Division for Bioinformatics, Biocenter, Medical University Innsbruck, Innrain 52, 6020, Innsbruck, Austria;Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, 6020, Innsbruck, Austria;Institute for Genomics and Bioinformatics, University of Technology, Petersgasse 14, 8010, Graz, Austria;

关键词: Aging;    Stress-induced senescence;    miR-101;    Ezh2;    Epigenetics;    UVB;   

DOI  :  10.1186/1471-2164-14-224

 received in 2012-03-29, accepted in 2013-03-08,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundCellular senescence can be induced by a variety of extrinsic stimuli, and sustained exposure to sunlight is a key factor in photoaging of the skin. Accordingly, irradiation of skin fibroblasts by UVB light triggers cellular senescence, which is thought to contribute to extrinsic skin aging, although molecular mechanisms are incompletely understood. Here, we addressed molecular mechanisms underlying UVB induced senescence of human diploid fibroblasts.ResultsWe observed a parallel activation of the p53/p21WAF1 and p16INK4a/pRb pathways. Using genome-wide transcriptome analysis, we identified a transcriptional signature of UVB-induced senescence that was conserved in three independent strains of human diploid fibroblasts (HDF) from skin. In parallel, a comprehensive screen for microRNAs regulated during UVB-induced senescence was performed which identified five microRNAs that are significantly regulated during the process. Bioinformatic analysis of miRNA-mRNA networks was performed to identify new functional mRNA targets with high confidence for miR-15a, miR-20a, miR-20b, miR-93, and miR-101. Already known targets of these miRNAs were identified in each case, validating the approach. Several new targets were identified for all of these miRNAs, with the potential to provide new insight in the process of UVB-induced senescence at a genome-wide level. Subsequent analysis was focused on miR-101 and its putative target gene Ezh2. We confirmed that Ezh2 is regulated by miR-101 in human fibroblasts, and found that both overexpression of miR-101 and downregulation of Ezh2 independently induce senescence in the absence of UVB irradiation. However, the downregulation of miR-101 was not sufficient to block the phenotype of UVB-induced senescence, suggesting that other UVB-induced processes induce the senescence response in a pathway redundant with upregulation of miR-101.ConclusionWe performed a comprehensive screen for UVB-regulated microRNAs in human diploid fibroblasts, and identified a network of miRNA-mRNA interactions mediating UVB-induced senescence. In addition, miR-101 and Ezh2 were identified as key players in UVB-induced senescence of HDF.

【 授权许可】

Unknown   
© Greussing et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.