Tristetraprolin specifically binds to intron regions and regulates alternative splicing of immune response genes in HeLa cells
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ABSTRACT:
PROVIDER: PRJNA533642 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8929420_1.fastq.gz | Fastqsanger.gz | |||
| SRR8929420_2.fastq.gz | Fastqsanger.gz | |||
| SRR8929417_1.fastq.gz | Fastqsanger.gz | |||
| SRR8929417_2.fastq.gz | Fastqsanger.gz | |||
| SRR8929418_1.fastq.gz | Fastqsanger.gz |
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Project description:Tristetraprolin (TTP) regulates inflammatory and immune responses by destabilizing target mRNAs via binding to their 3’-UTR AREs. However, we first found that TTP can regulate gene expression and alternative splicing of inflammatory and immune responses genes in the absence of stimulation. In order to find the regulatory mechanisms, we performed iRIP-seq experiments in HeLa cells. iRIP-seq study revealed that TTP binding sites are enriched in the CDS and intronic RNA regions. We also found that the TTP-targets genes were enriched in positive regulation of I-kappaB kinase/NF-kappaB cascade and positive regulation of NF-kappaB transcription factor activity pathway, such as STAT4, EGR3, RELB, TRIM22, RNF25, and TRAF1. Furthermore, we found that alternative splicing of the innate immune response genes were globally regulated by TTP in HeLa cells. Genome-wide mapping of TTP-RNA interactions now reveal that dominant TTP binding near a competing constitutive splice site, whereas prevalent binding close to an alternative site often causes intron retention. This positional effect was further demonstrated by disrupting a TTP-binding site on minigene constructs and detecting their AS events. These findings suggest a mechanism for TTP to modulate splice site competition to produce opposite functional consequences in HeLa cells.
2020-03-12 | GSE130053 | GEO
Project description:Tristetraprolin specifically regulates the expression and alternative splicing of immune response genes in Hela cells
| PRJNA470575 | ENA
Project description:we cloned and overexpressed human TTP-encoding gene ZFP36 in HeLa cell in the absence of inflammatory stimuli. The transcriptomes of the control and ZFP36-overexpression cells were sequenced and subjected to analysis and validation. Upon ZFP36 overexpression, expression of genes in innate immunity, including those in type I interferon signaling pathway and viral response, were specifically up-regulated, implying a transcriptional regulatory mechanism associated with the predicted DNA binding activity of TTP. TTP preferentially regulates the alternative splicing of genes involved in positive regulation of I-B/NF-B cascade and TRIF-dependent toll-like receptor signaling pathway, MAPK signaling pathway, TNF signaling pathway and T cell receptor signaling pathways.Our study indicates that TTP may regulates immune response via alternative splicing regulation and possibly by transcriptional regulation as well, which greatly expands the current understanding of the central role of TTP in regulating immune response and tumorigenesis.
2019-03-24 | GSE114216 | GEO
Project description:BackgroundTristetraprolin (TTP) is an RNA binding protein that plays a critical role in regulating proinflammatory immune responses by destabilizing target mRNAs via binding to their AU-rich elements (AREs) in the 3'-UTRs of mRNAs. A recent CLIP-seq study revealed that TTP-binding sites are enriched in the intronic regions of RNA. TTP is also a nuclear protein that exhibits putative DNA-binding activity. These features suggested that TTP might regulate gene transcription and/or alternative splicing of pre-mRNAs in the absence of stimulation.ResultsTo elucidate the regulatory pattern of TTP, we cloned and overexpressed the human TTP-encoding gene, ZFP36, in HeLa cells in the absence of inflammatory stimuli. The transcriptomes of the control and ZFP36-overexpressing cells were sequenced and subjected to analysis and validation. Upon ZFP36 overexpression, the expression of genes associated with innate immunity, including those in the type I interferon signaling pathway and viral response, were specifically upregulated, implying a transcriptional regulatory mechanism associated with the predicted DNA binding activity of TTP. TTP preferentially regulated the alternative splicing of genes involved in the positive regulation of the I-κB/NF-κB cascade and the TRIF-dependent toll-like receptor, MAPK, TNF, and T cell receptor signaling pathways.ConclusionsOur findings indicated that TTP may regulate the immune response via the regulation of alternative splicing and potentially transcription, which greatly expands the current understanding of the mechanisms of TTP-mediated gene regulation.
| S-EPMC6498542 | biostudies-literature
Project description:We identified a landscape of FUS-binding RNA targets in HeLa cells. The majority of the FUS binding sites are in introns of pre-mRNAs and less are in exons and untranslated regions. Significant FUS binding in introns flanking cassette exons, long intron (>100kb) containing transcripts and noncoding RNAs were detected in our study. We specifically determined the function of FUS in regulating the alternative splicing of cassette exons. The top FUS-associated cassette exon is exon 7 of the pre-mRNA of FUS itself. We demonstrated that FUS is a repressor of its own exon 7 splicing. FUS autoregulates its own protein levels by exon 7 alternative splicing and nonsense mediated decay. Moreover, Amyotrophic Lateral Sclerosis (ALS) linked FUS mutants are deficient in FUS autoregulation. CLIP-seq of FUS in HeLa cells
2013-12-16 | E-GEOD-50178 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE33474: Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [bone marrow B cells]. GSE37790: Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [Lymphoma]. GSE37791: Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [retrovirally infected ex vivo lymphoma] Refer to individual Series
2012-08-01 | E-GEOD-37792 | biostudies-arrayexpress
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. In this study, we evaluated the effects of TTP deficiency on the overall gene expression of spleen tissue, in order to discover tissue specific targets of TTP under normal physiologic conditions. We utilized "Triple KO" (Zfp36-/-/TNFR1-/-/TNFR2-/-) mice that are deficient in TTP and two TNF receptors and compared the transcriptomic changes to "Double KO" (TNFR1-/-/TNFR2-/-) and WT mice. Spleen mRNA from four WT, four "Double KO", and four "Triple mice" was subjected to RNA-Seq in two phases. All the animals used in this study were males between the ages of 12-14 weeks and were on a mixed (75% C57BL/6NTac, 25% 129/SVEV) background.
2016-03-27 | GSE60243 | 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. In this study, we evaluated the effects of TTP deficiency on the overall gene expression of spleen tissue, in order to discover tissue specific targets of TTP under normal physiologic conditions. We utilized "Triple KO" (Zfp36-/-/TNFR1-/-/TNFR2-/-) mice that are deficient in TTP and two TNF receptors and compared the transcriptomic changes to "Double KO" (TNFR1-/-/TNFR2-/-) and WT mice. Spleen mRNA from four WT, four "Double KO", and four "Triple mice" was subjected to RNA-Seq in two phases. All the animals used in this study were males between the ages of 12-14 weeks and were on a mixed (75% C57BL/6NTac, 25% 129/SVEV) background. Examination of splenic gene expression difference between "Triple KO"-WT and "double KO"-WT data sets
2016-03-27 | E-GEOD-60243 | biostudies-arrayexpress
Project description:We identified a landscape of FUS-binding RNA targets in HeLa cells. The majority of the FUS binding sites are in introns of pre-mRNAs and less are in exons and untranslated regions. Significant FUS binding in introns flanking cassette exons, long intron (>100kb) containing transcripts and noncoding RNAs were detected in our study. We specifically determined the function of FUS in regulating the alternative splicing of cassette exons. The top FUS-associated cassette exon is exon 7 of the pre-mRNA of FUS itself. We demonstrated that FUS is a repressor of its own exon 7 splicing. FUS autoregulates its own protein levels by exon 7 alternative splicing and nonsense mediated decay. Moreover, Amyotrophic Lateral Sclerosis (ALS) linked FUS mutants are deficient in FUS autoregulation.
2013-12-16 | GSE50178 | 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