Unknown,Transcriptomics,Genomics,Proteomics

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Pervasive TTP binding but selective target mRNA destabilization in the macrophage transcriptome [RNA-Seq_2]


ABSTRACT: Precise control of mRNA decay is fundamental for robust yet not exaggerated inflammatory responses to pathogens. Parameters determining the specificity and extent of mRNA degradation within the entire inflammation-associated transcriptome remain incompletely understood. Using transcriptome-wide high resolution occupancy assessment of the mRNA-destabilizing protein TTP, a major inflammation-limiting factor, we qualitatively and quantitatively characterize TTP binding positions and functionally relate them to TTP-dependent mRNA decay in immunostimulated macrophages. We identify pervasive TTP binding with incompletely penetrant linkage to mRNA destabilization. A necessary but not sufficient feature of TTP-mediated mRNA destabilization is binding to 3â?? untranslated regions (UTRs). Mapping of binding positions of the mRNA-stabilizing protein HuR in activated macrophages revealed that TTP and HuR binding sites in 3â?? UTRs occur mostly in different transcripts implicating only a limited co-regulation of inflammatory mRNAs by these proteins. Remarkably, we identify robust and widespread TTP binding to introns of stable transcripts. Nuclear TTP is associated with spliced-out introns and maintained in the nucleus throughout the inflammatory response. Our study establishes a functional annotation of binding positions dictating TTP-dependent mRNA decay in immunostimulated macrophages. The findings allow navigating the transcriptome-wide landscape of RNA elements controlling inflammation. Experiment comparing RNA decay rates in WT and TTP-/- macrophages at LPS 3 h and 6 h. Transcription was blocked with actinomycin D for 0, 45 or 90 min. Decay rates was calculated using linear model.

ORGANISM(S): Mus musculus

SUBMITTER: Vitaly Sedlyarov 

PROVIDER: E-GEOD-78209 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Sedlyarov Vitaly V   Fallmann Jörg J   Ebner Florian F   Huemer Jakob J   Sneezum Lucy L   Ivin Masa M   Kreiner Kristina K   Tanzer Andrea A   Vogl Claus C   Hofacker Ivo I   Kovarik Pavel P  

Molecular systems biology 20160513 5


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 im  ...[more]

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