Context-dependent IL-1 mRNA-destabilization by TTP prevents dysregulation of immune homeostasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA599384 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10843574.fastq.gz | Fastqsanger.gz | |||
| SRR10843575.fastq.gz | Fastqsanger.gz | |||
| SRR10843576.fastq.gz | Fastqsanger.gz | |||
| SRR10843577.fastq.gz | Fastqsanger.gz | |||
| SRR10843578.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
Project description:We report that TTP exhibits context-dependent target destabilisation and that such context-defined mRNA decay is essential for maintaining steady state IL-1 levels in the physiological range
2020-06-23 | GSE143241 | GEO
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
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
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
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
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 | GSE63466 | GEO
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
Project description:The bioavailability of the major pro-inflammatory cytokines IL-1α and IL-1β is tightly controlled by transcription and post-translational processing to prevent hyperinflammation. The role of mRNA decay in maintenance of physiological IL-1 amounts remained unknown. Here we show that the down-regulation of Il1a and Il1b mRNA by the mRNA-destabilizing protein TTP (gene Zfp36) is required for immune homeostasis. The TTP deficiency syndrome, a multi organ inflammation in TTP -/- mice, was significantly ameliorated upon deletion of the IL-1 receptor. Il1a and Il1b played non-redundant roles in triggering the pathological IL-1 signaling in TTP -/- mice. Accordingly, tissues from TTP -/- animals contained increased amounts of Il1b mRNA. Unexpectedly, TTP destabilized Il1b mRNA in cell type-specific ways as evident from RNA-Seq and mRNA stability assays. These results demonstrate that TTP-driven mRNA destabilization depends on the cellular context. Moreover, such context-defined mRNA decay is essential for keeping steady state IL-1 levels in the physiological range.
| S-EPMC7358311 | biostudies-literature
Project description:Successful immune responses are dependent on a precisely controlled balance between transcription and mRNA degradation. mRNA decay is driven through RNA-binding proteins (RBP), yet it remains unclear, how and when an individual mRNA molecule is selected for degradation. We investigated this fundamental question by using the anti-inflammatory RBP tristetraprolin (TTP, also known as Zfp36) as a model. Here, we show that TTP determines the fate of its targets concomitantly with their synthesis by binding to the pre-mRNA in the nucleus. Furthermore, we provide evidence that TTP orchestrates the target destabilization via a hierarchical molecular assembly that culminates by the association of mature mRNA with the RNA degradation machinery in the cytoplasm. The early fate decision in the life cycle of a TTP target mRNA prevents the translation of inflammatory mediators, particularly cytokine mRNAs, and promotes efficient cessation of the immune response. Importantly, the TTP homolog ZFP36L1 displays similar characteristics, suggesting a conserved mode of action within the ZFP36 family of RBPs.
2025-01-27 | PXD046381 | Pride
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