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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.

Author information

1
Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
2
Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria.
3
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
4
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 ivo.hofacker@univie.ac.at pavel.kovarik@univie.ac.at.
5
Max F. Perutz Laboratories, University of Vienna, Vienna, Austria ivo.hofacker@univie.ac.at pavel.kovarik@univie.ac.at.

Abstract

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 (http://ttp-atlas.univie.ac.at) of cis-acting elements controlling mRNA decay in inflammation.

KEYWORDS:

PAR‐CLIP; inflammation; mRNA decay; macrophage

PMID:
27178967
PMCID:
PMC4988506
[Indexed for MEDLINE]
Free PMC Article

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