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

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.

• Authors: Vitaly Sedlyarov, Jörg Fallmann, Florian Ebner, Jakob Huemer, Lucy Sneezum, Masa Ivin, Kristina Kreiner, Andrea Tanzer, Claus Vogl, Ivo Hofacker, Pavel Kovarik
• Journal: Molecular systems biology (Mol Syst Biol) Vol. 12 Issue 5 Pg. 868 (05 13 2016) ISSN: 1744-4292 [Electronic] England
• PMID: 27178967 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Lipopolysaccharides
• RNA, Messenger
• Tristetraprolin

Topics

• Animals
• Binding Sites
• Cells, Cultured
• Gene Expression Profiling (methods)
• Gene Expression Regulation
• HEK293 Cells
• Humans
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, immunology)
• Mice
• RNA Stability
• RNA, Messenger (chemistry, metabolism)
• Sequence Analysis, RNA
• Tristetraprolin (metabolism)