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

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. Synopsis A time‐resolved quantitative analysis of TTP binding sites, mRNA abundance, and mRNA stability in mouse macrophages generates a transcriptome‐wide atlas of cis ‐acting elements controlling mRNA decay in inflammation. A genome‐wide, high‐resolution, and time‐resolved analysis of TTP binding sites is performed in immunostimulated macrophages. “TTP atlas”, a functionally annotated collection of mapped TTP binding sites relating TTP binding to transcriptome‐wide differential mRNA decay rates and differential mRNA expression in WT and TTP‐deficient macrophages, is generated ( http://ttp-atlas.univie.ac.at ). Transcriptome‐wide analysis of mRNA stability and mRNA expression identifies a TTP‐driven switch initiating resolution of inflammation and indicates a limited co‐regulation of inflammatory mRNA decay by TTP and HuR. Graphical Abstract A time‐resolved quantitative analysis of TTP binding sites, mRNA abundance, and mRNA stability in mouse macrophages generates a transcriptome‐wide atlas of cis ‐acting elements controlling mRNA decay in inflammation.