TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation
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ABSTRACT:
PROVIDER: PRJNA662043 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12604032_1.fastq.gz | Fastqsanger.gz | |||
| SRR12604032_2.fastq.gz | Fastqsanger.gz | |||
| SRR12604033_1.fastq.gz | Fastqsanger.gz | |||
| SRR12604033_2.fastq.gz | Fastqsanger.gz | |||
| SRR12604034_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
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
Project description:Tristetraprolin (TTP), an important immunosuppressive protein regulating mRNA decay through recognition of 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 was upregulated in acute liver failure (ALF), resulting in decreased mRNA stabilities of CCL2 and CCL5 through promotion of N6-methyladenosine (m6A) mRNA methylation. Overexpression of TTP could markedly ameliorate hepatic injury in vivo. TTP regulated the mRNA stabilization of CCL2 and CCL5. Interestingly, increased m6A methylation in CCL2 and CCL5 mRNAs promoted TTP-mediated RNA destabilization. Moreover, induction of TTP upregulated expression levels of WT1 associated protein, methyltransferase like 14, and YT521-B homology N6-methyladenosine RNA binding protein 2, which encode enzymes regulating m6A methylation, resulting in a global increase of m6A methylation and amelioration of liver injury due to enhanced degradation of CCL2 and CCL5. These findings suggest a potentially novel mechanism by which TTP modulates mRNA stabilities of CCL2 and CCL5 through m6A RNA methylation, which is involved in the pathogenesis of ALF.
| S-EPMC8675193 | biostudies-literature
Project description:Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that was identified through its rapid induction by mitogens in fibroblasts. Studies of TTP-deficient mice, and cells derived from them, showed that TTP could bind to certain AU-rich elements in mRNAs, leading to increases in the rates of mRNA deadenylation and destruction. Known physiological target mRNAs for TTP include tumor necrosis factor alpha (TNF), granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin 2 beta (IL2 beta). Here we used microarray analysis of RNA from wild-type and TTP-deficient fibroblast cell lines to identify transcripts with different decay rates, after serum stimulation and actinomycin D treatment. Of 250 mRNAs apparently stabilized in the absence of TTP, 23 contained conserved TTP binding sites; 10 of these were shown by secondary analyses to be stabilized. The most dramatically affected transcript encoded the protein Ier3, recently implicated in the physiological control of blood pressure. The Ier3 transcript contained several conserved TTP binding sites that could bind TTP directly, and conferred TTP sensitivity to the mRNA in cell transfection studies. These studies have identified several new, physiologically relevant TTP target transcripts in fibroblasts; these target mRNAs encode proteins from a variety of functional classes. Keywords: mRNA degradation, time course, knockout experiment
2006-10-17 | GSE5324 | GEO
Project description:ATF4 Protects the Heart from Failure by Antagonizing Oxidative Stress
| PRJNA777255 | ENA
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
Project description:Tristetraprolin (TTP) binds to specific AU-rich elements in the 3'UTR of certain transcripts and regulates post-transcriptional gene expression by increasing the rate of mRNA turnover. Here, we generated a novel TTP mouse line (TTPΔARE) with a 136 base deletion in the 3'UTR AU-rich region of TTP mRNA, which resulted in a moderate increase in TTP protein expression in many tissues. In this study, we evaluated the effects of the moderate TTP overexpression on the overall pattern of gene expression in spleen, to investigate the effect of this mutation on mRNA targets of TTP under normal conditions. We utilized "TTPΔARE" (136 b deletion in the 3'UTR AU-rich region of Zfp36 mRNA) mice that overexpress TTP and compared the transcriptomic changes to the littermate "WT" mice. Spleen mRNA from four WT and four "TTPΔARE" mice were subjected to mRNA-Seq. All the animals used in this study were males between the ages of 8-12 weeks and were on a C57BL/6 background.
2019-01-19 | GSE65357 | GEO
Project description:Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that was identified through its rapid induction by mitogens in fibroblasts. Studies of TTP-deficient mice, and cells derived from them, showed that TTP could bind to certain AU-rich elements in mRNAs, leading to increases in the rates of mRNA deadenylation and destruction. Known physiological target; mRNAs for TTP include tumor necrosis factor alpha (TNF), granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin 2 beta (IL2 beta). Here we used microarray analysis of RNA from wild-type and TTP-deficient fibroblast cell lines to identify transcripts with different decay rates, after serum stimulation and actinomycin D treatment. Of 250 mRNAs apparently stabilized in the absence of TTP, 23 contained conserved TTP binding sites; 10 of these were shown by secondary analyses to be stabilized. The most dramatically affected transcript encoded the protein Ier3, recently implicated in the physiological control of blood pressure. The Ier3 transcript contained several conserved TTP binding sites that could bind TTP directly, and conferred TTP sensitivity to the mRNA in cell transfection studies. These studies have identified several new, physiologically relevant TTP target transcripts in fibroblasts; these target mRNAs encode proteins from a variety of functional classes. Experiment Overall Design: Cell lines were derived from mouse embryonic fibroblast (MEF) cultures from littermate E14.5 embryos (for Zfp36 +/+ and -/- cells). MEFs were maintained at 37o C (5% CO2) in DMEM containing 10% FBS, 100 Experiment Overall Design: U/ml penicillin, 100 μg/ml streptomycin and 2 mM L-glutamine. When the cells had reached approximately 70-90 % confluence, they were trypsinized and diluted 2-50 fold in the same medium, based on morphology and growth rate, such that they would reach near confluence in 3-4 days when subcultured. Experiment Overall Design: Five identical experiments involving sequential serum deprivation, serum stimulation and actinomycin D treatment were performed on five different days; each experiment involved simultaneous identical experiments with the WT and KO cell lines. In each experiment, the cells were serum deprived for 16h, and a sample was taken at that point as a serum-deprived control. The cells were then stimulated by 10% FBS for Experiment Overall Design: 90 min and another sample taken, after which 5μg/ml actinomycin D was added; samples for RNA analysis were then removed at 30, 60, 90 and 120 min after actinomycin D treatment. In all experiments, each sample represented three combined 100 mm dishes of cells.
2008-11-22 | E-GEOD-5324 | biostudies-arrayexpress
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. We compared mRNA stability in LPS-treated BMDMs from WT and TTP-/- mice by microarray-based measurement of the remnant mRNA after transcriptional blockade with actinomycin D (act D). To increase the sensitivity of the mRNA decay profiling we inhibited the LPS-activated p38 MAPK with the specific inhibitor SB203580 since p38 MAPK negatively regulates the mRNA-destabilizing activity of TTP. LPS stimulation was for 3h before addition of act D. RNA was harvested at 0', 45' and 90' thereafter.
2011-12-15 | E-GEOD-28880 | biostudies-arrayexpress
Project description:This study sought correlates of relapse tendency in TTP by examining gene expression profiles in peripheral blood leukocytes from patients with acquired ADAMTS13-deficient TTP in remission and matched healthy controls for global gene expression and autoantibodies. Total RNA was isolated from PAXgene RNA tubes from 39 patients with with acquired ADAMTS13-deficient TTP (all patients had relapsed) and 39 healthy controls.
2013-03-07 | E-GEOD-36418 | biostudies-arrayexpress
Project description:This study sought correlates of relapse tendency in TTP by examining gene expression profiles in peripheral blood leukocytes from patients with acquired ADAMTS13-deficient TTP in remission and matched healthy controls for global gene expression and autoantibodies.
2013-03-07 | GSE36418 | GEO