title: 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.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Sedlyarov
authors.affiliation: Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Jörg
authors.identifier: 0000-0002-4573-9939
authors.initials: J
authors.lastname: Fallmann
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Ebner
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Jakob
authors.initials: J
authors.lastname: Huemer
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Lucy
authors.initials: L
authors.lastname: Sneezum
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Masa
authors.initials: M
authors.lastname: Ivin
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Kristina
authors.initials: K
authors.lastname: Kreiner
authors.affiliation: Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tanzer
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Claus
authors.initials: C
authors.lastname: Vogl
authors.affiliation: 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.
authors.forename: Ivo
authors.identifier: 0000-0001-7132-0800
authors.initials: I
authors.lastname: Hofacker
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria ivo.hofacker@univie.ac.at pavel.kovarik@univie.ac.at.
authors.forename: Pavel
authors.identifier: 0000-0003-2956-0944
authors.initials: P
authors.lastname: Kovarik
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D051816:Tristetraprolin / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051816:Tristetraprolin
keywords: PAR‐CLIP; inflammation; mRNA decay; macrophage