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Pervasive TTP binding but selective target mRNA destabilization in the macrophage transcriptome [PAR-iCLIP]

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 3’ untranslated regions (UTRs). Mapping of binding positions of the mRNA-stabilizing protein HuR in activated macrophages revealed that TTP and HuR binding sites in 3’ 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE63466 | GEO | 2016/05/17

SECONDARY ACCESSION(S): PRJNA267848

REPOSITORIES: GEO

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Pervasive TTP binding but selective target mRNA destabilization in the macrophage transcriptome [PAR-iCLIP]

Project description: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. PAR-iCLIP for TTP (3 replicates) and for HuR (2 replicates)

2016-05-17 | E-GEOD-63466 | biostudies-arrayexpress

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

Project description: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. RNA-Seq of RNA isolated from murine bone marrow derived macrophages (WT or TTP-deficient) stimulated for 6 h with LPS

2016-05-17 | E-GEOD-63467 | biostudies-arrayexpress

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

Project description: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.

2016-05-17 | E-GEOD-78209 | biostudies-arrayexpress

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

Project description: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 3’ untranslated regions (UTRs). Mapping of binding positions of the mRNA-stabilizing protein HuR in activated macrophages revealed that TTP and HuR binding sites in 3’ 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.

2016-05-17 | GSE63467 | GEO

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

Project description: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 3’ untranslated regions (UTRs). Mapping of binding positions of the mRNA-stabilizing protein HuR in activated macrophages revealed that TTP and HuR binding sites in 3’ 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.

2016-05-17 | GSE78209 | GEO

TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation

Project description:Tristetraprolin (TTP), an important immunosuppressive protein regulating mRNA decay through recognizing the AU-rich elements (AREs) within the 3’UTRs of mRNAs, participates in the pathogenesis of liver diseases. However, whether TTP regulates mRNA stability through other mechanisms remains poorly understood. Here, we report that TTP is upregulated in acute liver failure (ALF), resulting in decreased mRNA stabilities of C-C Motif Chemokine Ligand 2 (CCL2) and C-C Motif Chemokine Ligand 5 (CCL5) through promoting N6-methyladenosine (m6A) mRNA methylation. Overexpression of TTP can markedly ameliorate hepatic injury in vivo. TTP regulates the mRNA stabilization of CCL2 and CCL5. Interestingly, increased m6A methylation in CCL2 and CCL5 mRNAs promotes TTP-mediated RNA destabilization. Moreover, induction of TTP upregulates expression levels of WT1 associated protein (WTAP), Methyltransferase like 14 (METTL14), and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), which encode enzymes regulating m6A methylation, resulting in a global increase of m6A methylation and amelioration of live injury due to enhanced degradation of CCL2 and CCL5. These findings suggest a novel mechanism by which TTP modulates mRNA stabilities of CCL2 and CCL5 through m6A RNA methylation, which is involved in the pathogenesis of ALF.

2021-11-08 | GSE157581 | GEO

RNA CLIP-seq for Cugbp1, Mbnl1 and Ptbp1 in mouse C2C12 myoblasts

Project description:CUG-binding protein 1 (CUGBP1) and muscleblind-like 1 (MBNL1) are developmentally regulated RNA-binding proteins that are causally associated with myotonic dystrophy type 1. We extensively determined RNA-binding sites of CUGBP1 and MBNL1 to investigate their roles in RNA processing. We also analyzed polypyrimidine tract-binding protein (PTB) as a control. CUGBP1 and MBNL1 preferentially bind to alternatively spliced introns and exons, respectively, and regulate alternative splicing events. Moreover, CUGBP1 and MBNL1 are preferentially bound to the 3' untranslated regions (UTRs), in particular of genes for RNA-binding proteins, and facilitate decay of the bound mRNAs. In addition, CUGBP1 and MBNL1 mutually destabilize mRNA. Precise temporal regulation of CUGBP1 and MBNL1 are likely to be essential for accurate control of destabilization of a broad spectrum of genes as well as of alternative splicing events in cell differentiation and tissue development.

2012-01-04 | E-MTAB-414 | biostudies-arrayexpress

Destabilization of Nucleophosmin mRNA by the HuR/KSRP complex is required for muscle fiber formation

Project description:HuR promotes myogenesis by stabilizing MyoD, Myogenin and p21 mRNAs during the fusion step of muscle cells to form myotubes. Here we show that HuR, via a novel mRNA destabilizing activity, promotes the early steps of myogenesis by reducing the expression of the cell cycle promoter nucleophosmin (NPM). Depletion of HuR stabilizes the NPM mRNA, increases NPM protein levels and inhibits myogenesis, while its overexpression elicits the opposite effects. NPM mRNA destabilization involves the association of HuR with the decay factor KSRP as well as the ribonuclease PARN and the exosome complex. The C-terminus of HuR mediates the formation of the HuR-KSRP complex and is sufficient for maintaining a low level of the NPM mRNA as well as promoting the commitment of muscle cells to myogenesis. We therefore propose a model whereby the downregulation of the NPM mRNA, mediated by the HuR/KSRP complex and its associated ribonucleases, is required for proper myogenesis. RNA was extracted from C2C12 treated with siRNA against HuR and compared to control siRNA

2014-04-26 | E-GEOD-57113 | biostudies-arrayexpress

Destabilization of Nucleophosmin mRNA by the HuR/KSRP complex is required for muscle fiber formation

2014-04-26 | GSE57113 | GEO

TTP-dependent mRNA decay in LPS-stimulated macrophages

Project description:Controlled decay of cytokine and chemokine mRNAs restrains the time and amplitude of inflammatory responses. Tristetraprolin (TTP) binds to AU-rich elements in 3´ untranslated regions of mRNA and targets the bound mRNA for degradation. We have addressed here the function of TTP in balancing the macrophage activation state by a comprehensive analysis of TTP-dependent mRNA decay in LPS-stimulated macrophages from WT and TTP-deficient mice.

2011-12-15 | GSE28880 | GEO

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