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

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


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.

Keywords: PAR‐CLIP; inflammation; mRNA decay; macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Lipopolysaccharides
  • RNA, Messenger
  • Tristetraprolin