Widespread context dependency of microRNA-mediated regulation

Florian Erhard, Jürgen Haas, Diana Lieber, Georg Malterer, Lukasz Jaskiewicz, Mihaela Zavolan, Lars Doelken*, Ralf Zimmer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)906-919
Number of pages14
JournalGenome Research
Volume24
Issue number6
Early online date25 Mar 2014
DOIs
Publication statusPublished - Jun 2014

Keywords

  • DIFFERENTIAL EXPRESSION ANALYSIS
  • TARGET MESSENGER-RNA
  • GENE-EXPRESSION
  • TRANSLATIONAL REPRESSION
  • TRANSCRIPTION FACTORS
  • BINDING PROTEINS
  • PAR-CLIP
  • IDENTIFICATION
  • SITES
  • RECOGNITION

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