title: Widespread context dependency of microRNA-mediated regulation.
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.
authors.affiliation: Institut für Informatik, Ludwig-Maximilians-Universität München, 80333 München, Germany;
authors.forename: Florian
authors.initials: F
authors.lastname: Erhard
authors.affiliation: Max-von-Pettenkofer Institut, Virologie, Ludwig-Maximilians-Universität München, 80336 München, Germany; Division of Pathway Medicine, University of Edinburgh, Edinburgh EH17 8TR, United Kingdom;
authors.forename: Jürgen
authors.initials: J
authors.lastname: Haas
authors.affiliation: Max-von-Pettenkofer Institut, Virologie, Ludwig-Maximilians-Universität München, 80336 München, Germany; Institut für Virologie, Universitätsklinikum Ulm, 89081 Ulm, Germany;
authors.forename: Diana
authors.initials: D
authors.lastname: Lieber
authors.affiliation: Max-von-Pettenkofer Institut, Virologie, Ludwig-Maximilians-Universität München, 80336 München, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Malterer
authors.affiliation: Biozentrum, University of Basel and Swiss Institute of Bioinformatics, CH-4056 Basel, Switzerland;
authors.forename: Lukasz
authors.initials: L
authors.lastname: Jaskiewicz
authors.affiliation: Biozentrum, University of Basel and Swiss Institute of Bioinformatics, CH-4056 Basel, Switzerland;
authors.forename: Mihaela
authors.initials: M
authors.lastname: Zavolan
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrookes Hospital, CB20QQ Cambridge, United Kingdom.
authors.forename: Lars
authors.initials: L
authors.lastname: Dölken
authors.affiliation: Institut für Informatik, Ludwig-Maximilians-Universität München, 80333 München, Germany;
authors.forename: Ralf
authors.initials: R
authors.lastname: Zimmer
mesh_terms: D045744:Cell Line, Tumor; D017124:Conserved Sequence; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D015894:Genome, Human; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D059372:Nucleotide Motifs; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger