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Global regulation of neuronal transcriptome by miR-9/tristetraprolin circuitry

ABSTRACT: Nervous system (NS) development relies on coherent up-regulation of extensive sets of genes in a precise spatiotemporal manner. How such transcriptome-wide effects are orchestrated at the molecular level remains an open question. Here we show that 3’-untranslated regions (3’UTRs) of multiple neuronal transcripts contain A/U-rich cis-elements (AREs) recognized by tristetraprolin (TTP/Zfp36), an RNA-binding protein previously reported to destabilize mRNAs encoding predominantly cytokines, growth factors and proto-oncogenes. We further demonstrate that the efficiency of ARE-dependent mRNA degradation declines during neural differentiation due to a decrease in the TTP protein expression mediated by the NS-enriched microRNA miR-9. Our experiments with transgenenic cell lines suggest that TTP down-regulation is essential for proper neuronal differentiation. Moreover, inactivation of TTP in neuroblastoma cells or mouse embryonic fibroblasts induces major changes in their transcriptomes accompanied by significantly elevated expression of NS-specific genes. We conclude that the newly identified miR-9/TTP circuitry limits unscheduled accumulation of neuronal mRNAs in non-neuronal cells and ensures coordinated up-regulation of these transcripts in neurons.

ORGANISM(S): Mus musculus

PROVIDER: GSE61098 | GEO | 2015/04/01

SECONDARY ACCESSION(S): PRJNA260219

REPOSITORIES: GEO

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Global regulation of neuronal transcriptome by miR-9/tristetraprolin circuitry

Project description:Nervous system (NS) development relies on coherent up-regulation of extensive sets of genes in a precise spatiotemporal manner. How such transcriptome-wide effects are orchestrated at the molecular level remains an open question. Here we show that 3’-untranslated regions (3’UTRs) of multiple neuronal transcripts contain A/U-rich cis-elements (AREs) recognized by tristetraprolin (TTP/Zfp36), an RNA-binding protein previously reported to destabilize mRNAs encoding predominantly cytokines, growth factors and proto-oncogenes. We further demonstrate that the efficiency of ARE-dependent mRNA degradation declines during neural differentiation due to a decrease in the TTP protein expression mediated by the NS-enriched microRNA miR-9. Our experiments with transgenenic cell lines suggest that TTP down-regulation is essential for proper neuronal differentiation. Moreover, inactivation of TTP in neuroblastoma cells or mouse embryonic fibroblasts induces major changes in their transcriptomes accompanied by significantly elevated expression of NS-specific genes. We conclude that the newly identified miR-9/TTP circuitry limits unscheduled accumulation of neuronal mRNAs in non-neuronal cells and ensures coordinated up-regulation of these transcripts in neurons. 3'READS of undifferentiated and 3.5-day differentiated P19 cells

2015-04-01 | E-GEOD-61098 | biostudies-arrayexpress

Tristetraprolin specifically binds to intron regions and regulates alternative splicing of immune response genes in HeLa cells

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

Tristetraprolin expression by keratinocytes protects against skin carcinogenesis

Project description:Cancer is caused primarily by somatic mutations of proto-oncogenes, leading to deregulation of gene regulatory circuits in key growth, apoptosis or DNA repair pathways. Multiple genes associated with the initiation and development of tumors are also regulated at the level of mRNA decay, through the recruitment of RNA binding proteins to AU-rich elements (AREs) located in their 3’-untranslated regions. One of these ARE-binding proteins, tristetraprolin (TTP, encoded by Zfp36) is consistently dysregulated in many human malignancies. Herein, using regulated overexpression or conditional ablation in the context of chemical cutaneous carcinogenesis, we show that TTP represents a critical regulator of skin tumorigenesis. We provide evidence that TTP controls both tumor-associated inflammation and key oncogenic pathways in malignant epidermal cells. We identify Areg as a direct target of TTP in keratinocytes, and show that EGFR signaling contributes to exacerbated tumor formation. We conclude that TTP expression by epidermal cells plays a major role in the control of early steps leading to tumorigenesis.

2021-04-13 | GSE151587 | GEO

Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [Lymphoma].

Project description:Myc oncoproteins directly regulate transcription by binding to target genes, yet this only explains a fraction of the genes affected by Myc. mRNA turnover is controlled via AU-binding proteins (AUBPs) that recognize AU-rich elements (AREs) found within many transcripts. Analyses of precancerous and malignant Myc-expressing B cells revealed that Myc regulates hundreds of ARE-containing (ARED) genes and select AUBPs. Notably, Myc directly suppresses transcription of Tristetraprolin (TTP/ZFP36), an mRNA-destabilizing AUBP, and this circuit is also operational during B lymphopoiesis and IL7 signaling. Importantly, TTP suppression is a hallmark of cancers with MYC involvement, and restoring TTP impairs Myc-induced lymphomagenesis and abolishes maintenance of the malignant state. Further, there is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor. Finally, Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis. Thus, Myc targets AUBPs to regulate ARED genes that control tumorigenesis. Lymphomas collected from EÎ¼-Myc and EÎ¼-Myc;EÂµ-TTP-1 transgenic mice were investigated. These samples were used for subsequent RNA purification, labeling and hybridization to MOE430 2.0 Affymetrix arrays.

2012-08-01 | E-GEOD-37790 | biostudies-arrayexpress

Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [Lymphoma].

2012-08-02 | GSE37790 | GEO

Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [retrovirally infected ex vivo lymphoma]

Project description:Myc oncoproteins directly regulate transcription by binding to target genes, yet this only explains a fraction of the genes affected by Myc. mRNA turnover is controlled via AU-binding proteins (AUBPs) that recognize AU-rich elements (AREs) found within many transcripts. Analyses of precancerous and malignant Myc-expressing B cells revealed that Myc regulates hundreds of ARE-containing (ARED) genes and select AUBPs. Notably, Myc directly suppresses transcription of Tristetraprolin (TTP/ZFP36), an mRNA-destabilizing AUBP, and this circuit is also operational during B lymphopoiesis and IL7 signaling. Importantly, TTP suppression is a hallmark of cancers with MYC involvement, and restoring TTP impairs Myc-induced lymphomagenesis and abolishes maintenance of the malignant state. Further, there is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor. Finally, Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis. Thus, Myc targets AUBPs to regulate ARED genes that control tumorigenesis. Ex vivo Eμ-Myc lymphoma cells were infected with MSCV-I-dsRed2 (RFP) and FACS sorted for dsRed2+ cells. These cells were then infected with MSCV-TTP-I-GFP and FACS sorted for GFP expression (TTP-GFP- or TTP-GFP+). These cells were used for subsequent RNA purification, labeling and hybridization to MOE430 2.0 Affymetrix arrays.

2012-08-01 | E-GEOD-37791 | biostudies-arrayexpress

Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [bone marrow B cells].

Project description:Myc oncoproteins directly regulate transcription by binding to target genes, yet this only explains a fraction of the genes affected by Myc. mRNA turnover is controlled via AU-binding proteins (AUBPs) that recognize AU-rich elements (AREs) found within many transcripts. Analyses of precancerous and malignant Myc-expressing B cells revealed that Myc regulates hundreds of ARE-containing (ARED) genes and select AUBPs. Notably, Myc directly suppresses transcription of Tristetraprolin (TTP/ZFP36), an mRNA-destabilizing AUBP, and this circuit is also operational during B lymphopoiesis and IL7 signaling. Importantly, TTP suppression is a hallmark of cancers with MYC involvement, and restoring TTP impairs Myc-induced lymphomagenesis and abolishes maintenance of the malignant state. Further, there is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor. Finally, Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis. Thus, Myc targets AUBPs to regulate ARED genes that control tumorigenesis. Wild type, Eµ-TTP-1, precancerous Eμ-Myc and precancerous Eμ-Myc;Eµ-TTP-1 transgenic bone marrow B cells (from 4-6 week old littermates; 94% C57BL/6) were investigated. These samples were used for subsequent RNA purification, labeling and hybridization to MOE430 2.0 Affymetrix arrays.

2012-08-01 | E-GEOD-33474 | biostudies-arrayexpress

Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [bone marrow B cells].

2012-08-02 | GSE33474 | GEO

Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [retrovirally infected ex vivo lymphoma]

2012-08-02 | GSE37791 | GEO

Tristetraprolin targets Nos2 expression in the colonic epithelium

Project description:Tristetraprolin (TTP), encoded by the Zfp36 gene, is a zinc-finger protein that regulates RNA stability primarily through association with 3’ untranslated regions (3’UTRs) of target mRNAs. While TTP is expressed abundantly in the intestines, its function in intestinal epithelial cells (IECs) is unknown. Here we used a cre-lox system to remove Zfp36 in the mouse epithelium to uncover a role for TTP in IECs and to identify target genes in these cells. While TTP was largely dispensable for establishment and maintenance of the colonic epithelium, we found an expansion of the proliferative zone and an increase in goblet cell numbers in the colon crypts of Zfp36ΔIEC mice. Furthermore, through RNA-sequencing of transcripts isolated from the colons of Zfp36fl/fl and Zfp36ΔIEC mice, we found that expression of inducible nitric oxide synthase (iNos or Nos2) was elevated in TTP-knockout IECs. We demonstrate that TTP interacts with AU-rich elements in the Nos2 3’UTR and suppresses Nos2 expression. In comparison to control Zfp36fl/fl mice, Zfp36ΔIEC mice were less susceptible to dextran sodium sulfate (DSS)-induced acute colitis. Together, these results demonstrate that TTP targets Nos2 expression in IECs and aggravates acute colitis.

2019-12-04 | GSE123345 | GEO

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