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Mol Syst Biol. 2016 May 13;12(5):868. doi: 10.15252/msb.20156628.

Tristetraprolin binding site atlas in the macrophage transcriptome reveals a switch for inflammation resolution.

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Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria Research Group Bioinformatics and Computational Biology, Faculty of Computer Science, University of Vienna, Vienna, Austria Center for non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg C, Denmark
Max F. Perutz Laboratories, University of Vienna, Vienna, Austria


Precise regulation of mRNA decay is fundamental for robust yet not exaggerated inflammatory responses to pathogens. However, a global model integrating regulation and functional consequences of inflammation-associated mRNA decay remains to be established. Using time-resolved high-resolution RNA binding analysis of the mRNA-destabilizing protein tristetraprolin (TTP), an inflammation-limiting factor, we qualitatively and quantitatively characterize TTP binding positions in the transcriptome of immunostimulated macrophages. We identify pervasive destabilizing and non-destabilizing TTP binding, including a robust intronic binding, showing that TTP binding is not sufficient for mRNA destabilization. A low degree of flanking RNA structuredness distinguishes occupied from silent binding motifs. By functionally relating TTP binding sites to mRNA stability and levels, we identify a TTP-controlled switch for the transition from inflammatory into the resolution phase of the macrophage immune response. Mapping of binding positions of the mRNA-stabilizing protein HuR reveals little target and functional overlap with TTP, implying a limited co-regulation of inflammatory mRNA decay by these proteins. Our study establishes a functionally annotated and navigable transcriptome-wide atlas ( of cis-acting elements controlling mRNA decay in inflammation.


PAR‐CLIP; inflammation; mRNA decay; macrophage

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