Tristetraprolin binding site atlas in the macrophage transcriptome reveals a switch for inflammation resolution
| Autor: | Sedlyarov, Vitaly, Fallmann, Jörg, Ebner, Florian, Huemer, Jakob, Sneezum, Lucy, Ivin, Masa, Kreiner, Kristina, Tanzer, Andrea, Vogl, Claus, Hofacker, Ivo, Kovarik, Pavel |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Lipopolysaccharides
Binding Sites Sequence Analysis RNA Gene Expression Profiling Macrophages RNA Stability Articles Methods & Resources macrophage PAR‐CLIP respiratory system RNA Biology Article Mice HEK293 Cells Gene Expression Regulation Tristetraprolin mRNA decay inflammation hemic and lymphatic diseases Genome-Scale & Integrative Biology Animals Humans RNA Messenger Cells Cultured |
| Zdroj: | Molecular Systems Biology |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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