Widespread context dependency of microRNA-mediated regulation
- Florian Erhard1,
- Jürgen Haas2,3,
- Diana Lieber2,4,
- Georg Malterer2,
- Lukasz Jaskiewicz5,
- Mihaela Zavolan5,
- Lars Dölken6,7 and
- Ralf Zimmer1,7
- 1Institut für Informatik, Ludwig-Maximilians-Universität München, 80333 München, Germany;
- 2Max-von-Pettenkofer Institut, Virologie, Ludwig-Maximilians-Universität München, 80336 München, Germany;
- 3Division of Pathway Medicine, University of Edinburgh, Edinburgh EH17 8TR, United Kingdom;
- 4Institut für Virologie, Universitätsklinikum Ulm, 89081 Ulm, Germany;
- 5Biozentrum, University of Basel and Swiss Institute of Bioinformatics, CH-4056 Basel, Switzerland;
- 6Department of Medicine, University of Cambridge, Addenbrookes Hospital, CB20QQ Cambridge, United Kingdom
Abstract
Gene expression is regulated in a context-dependent, cell-type-specific manner. Condition-specific transcription is dependent on the presence of transcription factors (TFs) that can activate or inhibit its target genes (global context). Additional factors, such as chromatin structure, histone, or DNA modifications, also influence the activity of individual target genes (individual context). The role of the global and individual context for post-transcriptional regulation has not systematically been investigated on a large scale and is poorly understood. Here we show that global and individual context dependency is a pervasive feature of microRNA-mediated regulation. Our comprehensive and highly consistent data set from several high-throughput technologies (PAR-CLIP, RIP-chip, 4sU-tagging, and SILAC) provides strong evidence that context-dependent microRNA target sites (CDTS) are as frequent and functionally relevant as constitutive target sites (CTS). Furthermore, we found the global context to be insufficient to explain the CDTS, and that flanking sequence motifs provide individual context that is an equally important factor. Our results demonstrate that, similar to TF-mediated regulation, global and individual context dependency are prevalent in microRNA-mediated gene regulation, implying a much more complex post-transcriptional regulatory network than is currently known. The necessary tools to unravel post-transcriptional regulations and mechanisms need to be much more involved, and much more data will be needed for particular cell types and cellular conditions in order to understand microRNA-mediated regulation and the context-dependent post-transcriptional regulatory network.
Footnotes
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↵7 Corresponding authors
E-mail ld408{at}medschl.cam.ac.uk
E-mail zimmer{at}bio.ifi.lmu.de
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.166702.113.
- Received September 13, 2013.
- Accepted March 24, 2014.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
