Email updates

Keep up to date with the latest news and content from BMC Genomics and BioMed Central.

Open Access Highly Accessed Research article

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

Ruth Greussing1, Matthias Hackl2, Pornpimol Charoentong3, Alexander Pauck1, Rossella Monteforte2, Maria Cavinato1, Edith Hofer3, Marcel Scheideler4, Michael Neuhaus1, Lucia Micutkova1, Christoph Mueck1, Zlatko Trajanoski3, Johannes Grillari25 and Pidder Jansen-Dürr1*

Author Affiliations

1 Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, Innsbruck 6020, Austria

2 Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, Vienna 1190, Austria

3 Division for Bioinformatics, Biocenter, Medical University Innsbruck, Innrain 52, Innsbruck 6020, Austria

4 Institute for Genomics and Bioinformatics, University of Technology, Petersgasse 14, Graz 8010, Austria

5 Evercyte GmbH, Muthgasse 18, Vienna, A 1190, Austria

For all author emails, please log on.

BMC Genomics 2013, 14:224  doi:10.1186/1471-2164-14-224

Published: 4 April 2013

Abstract

Background

Cellular 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.

Results

We 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.

Conclusion

We 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.

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