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Global Target mRNA Specification and Regulation by RNA-Binding Protein ZFP36/Tristetraprolin/TTP [PAR-CLIP]

ABSTRACT: Tristetraprolin/ZFP36/TTP and ELAVL1/HuR are two disease-relevant RNA-binding proteins (RBPs) that both interact with AU-rich sequences but have antagonistic roles. While ELAVL1 binding has been profiled in several studies, the precise in vivo binding specificity of ZFP36 has not been investigated on a global scale. We determined ZFP36 binding preferences using cross-linking and immunoprecipitation in human embyonic kidney cells and examined combinatorial regulation of AU-rich elements by ZFP36 and ELAVL1. Among the targets ZFP36 binds and negatively regulates the mRNA of genes encoding proteins necessary for immune function and cancer, and other RBPs. Using partial correlation analysis, we were able to quantify the association between ZFP36 binding sites and differential target RNA abundance from ZFP36 overexpression independent of effects from confounding features, such as 3’ UTR length. We identified thousands of overlapping ZFP36 and ELAVL1 binding sites, in 1,313 genes. ZFP36 preferentially interacts with and regulates AU-rich sequences while ELAVL1 prefers predominantly U- and CU-rich sequences. RNA target specificity identified by global in vivo ZFP36-mRNA interactions were quantitatively similar to previously reported in vitro binding affinities. ZFP36 and ELAVL1 both bind an overlapping spectrum of RNA sequences, yet with differential relative preferences that dictate combinatorial regulatory potential. Our findings and methodology delineate an approach to untangle the in vivo combinatorial regulation by RNA-binding proteins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53184 | GEO | 2013/12/24

SECONDARY ACCESSION(S): PRJNA231063

REPOSITORIES: GEO

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Global Target mRNA Specification and Regulation by RNA-Binding Protein ZFP36/Tristetraprolin/TTP [PAR-CLIP]

Project description:Tristetraprolin/ZFP36/TTP and ELAVL1/HuR are two disease-relevant RNA-binding proteins (RBPs) that both interact with AU-rich sequences but have antagonistic roles. While ELAVL1 binding has been profiled in several studies, the precise in vivo binding specificity of ZFP36 has not been investigated on a global scale. We determined ZFP36 binding preferences using cross-linking and immunoprecipitation in human embyonic kidney cells and examined combinatorial regulation of AU-rich elements by ZFP36 and ELAVL1. Among the targets ZFP36 binds and negatively regulates the mRNA of genes encoding proteins necessary for immune function and cancer, and other RBPs. Using partial correlation analysis, we were able to quantify the association between ZFP36 binding sites and differential target RNA abundance from ZFP36 overexpression independent of effects from confounding features, such as 3M-bM-^@M-^Y UTR length. We identified thousands of overlapping ZFP36 and ELAVL1 binding sites, in 1,313 genes. ZFP36 preferentially interacts with and regulates AU-rich sequences while ELAVL1 prefers predominantly U- and CU-rich sequences. RNA target specificity identified by global in vivo ZFP36-mRNA interactions were quantitatively similar to previously reported in vitro binding affinities. ZFP36 and ELAVL1 both bind an overlapping spectrum of RNA sequences, yet with differential relative preferences that dictate combinatorial regulatory potential. Our findings and methodology delineate an approach to untangle the in vivo combinatorial regulation by RNA-binding proteins. FLAG-HA ZFP36

2013-12-24 | E-GEOD-53184 | biostudies-arrayexpress

Global Target mRNA Specification and Regulation by RNA-Binding Protein ZFP36/Tristetraprolin/TTP [Affymetrix]

2013-12-24 | E-GEOD-53183 | biostudies-arrayexpress

Global Target mRNA Specification and Regulation by RNA-Binding Protein ZFP36/Tristetraprolin/TTP [Affymetrix]

Project description:Tristetraprolin/ZFP36/TTP and ELAVL1/HuR are two disease-relevant RNA-binding proteins (RBPs) that both interact with AU-rich sequences but have antagonistic roles. While ELAVL1 binding has been profiled in several studies, the precise in vivo binding specificity of ZFP36 has not been investigated on a global scale. We determined ZFP36 binding preferences using cross-linking and immunoprecipitation in human embyonic kidney cells and examined combinatorial regulation of AU-rich elements by ZFP36 and ELAVL1. Among the targets ZFP36 binds and negatively regulates the mRNA of genes encoding proteins necessary for immune function and cancer, and other RBPs. Using partial correlation analysis, we were able to quantify the association between ZFP36 binding sites and differential target RNA abundance from ZFP36 overexpression independent of effects from confounding features, such as 3’ UTR length. We identified thousands of overlapping ZFP36 and ELAVL1 binding sites, in 1,313 genes. ZFP36 preferentially interacts with and regulates AU-rich sequences while ELAVL1 prefers predominantly U- and CU-rich sequences. RNA target specificity identified by global in vivo ZFP36-mRNA interactions were quantitatively similar to previously reported in vitro binding affinities. ZFP36 and ELAVL1 both bind an overlapping spectrum of RNA sequences, yet with differential relative preferences that dictate combinatorial regulatory potential. Our findings and methodology delineate an approach to untangle the in vivo combinatorial regulation by RNA-binding proteins.

2013-12-24 | GSE53183 | GEO

ZFP36 RNA binding proteins restrain T-cell activation and anti-viral immunity [HITS-CLIP]

Project description:Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoimmunity and cancer, but functions in adaptive immunity are less clear. We used HITS-CLIP to define ZFP36 targets in T-cells, which confirmed regulation of cytokine expression and revealed unanticipated actions in regulating T-cell activation and proliferation. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, most robustly through a novel class of AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T-cell activation kinetics by attenuating activation marker expression, limiting T-cell expansion, and promoting apoptosis in a cell autonomous manner. Strikingly, loss of ZFP36 in vivo accelerated T-cell responses to acute viral infection, and enhanced anti-viral immunity. These findings uncover a critical role for ZFP36 RBPs in restraining T-cell expansion and effector functions, and suggest ZFP36 inhibition as a novel strategy to enhance immune-based therapies.

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ZFP36 RNA binding proteins restrain T-cell activation kinetics and anti-viral immunity [ribo-seq]

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ZFP36 RNA binding proteins restrain T-cell activation kinetics and anti-viral immunity [RNA-seq]

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Project description:Post-transcriptional gene regulation by miRNAs and RNA binding proteins (RBP) is important in development, physiology and disease. To examine the interplay between miRNAs and the RBP ELAVL1 (a.k.a. HuR), we mapped miRNA binding sites on a transcriptome-wide scale in WT and Elavl1 knockout murine bone marrow-derived macrophages. Proximity of ELAVL1 binding sites attenuated miRNA binding to transcripts and promoted gene expression. Transcripts that regulate angiogenesis and macrophage/ endothelial cross talk were preferentially targeted by miRNAs, suggesting that ELAVL1 promotes angiogenesis, at least in part, by antagonism of miRNA function. We found that ELAVL1 antagonized binding of miR-27 to the 3’UTR of Zfp36 mRNA and alleviated miR-27-mediated suppression of the RBP ZFP36 (a.k.a. Tristetraprolin). Thus the miR-27-regulated mechanism synchronizes the expression of ELAVL1 and ZFP36. This study provides a resource for systems-level interrogation of post-transcriptional gene regulation in macrophages, a key cell type in inflammation, angiogenesis and tissue homeostasis. Bone marrow derived macrpohges mRNA profiles of 7-day cultured wild type (WT) and Elavl1l-/- mouse bone marrow cells were generated by deep sequencing, with 4 biologic duplication, using Illumina GAII.

2015-04-23 | E-GEOD-63199 | biostudies-arrayexpress

ELAVL1 modulates transcriptome-wide miRNA binding in murine macrophages

2015-04-23 | GSE63199 | GEO

The effect of ZFP36L1 deficiency on gene expression in the U2OS osteosarcoma cancer cell line

Project description:Post-transcriptional regulation of gene expression by RNA binding proteins (RBPs), one of the major classes of proteins encoded by the human genome, is well established. ZFP36L1 and its protein family members, ZFP36 and ZFP36L2, function as RBPs that primarily regulate gene expression at the post-transcriptional level by binding to adenine uridine (AU) rich elements (AREs) in the 3′ untranslated region (3′UTR) of certain mRNAs and mediating ARE-dependent mRNA decay. In this study, using CRISPR/Cas9 ZFP36L1 gene-editing, we generated ZFP36L1 deficient U2OS cellular models. The aim of the RNASeq experiment was to compare the gene expression profile in wild-type U2OS cells compared to ZFP36L1 deficient U2OS cells. Loss of functional ZFP36L1 leads to widespread changes in gene expression that are associated with dysregulation of KRAS signalling.

2024-06-04 | GSE268088 | GEO

Biotin-pgRNAWT or Biotin-pgRNAAUUUA to AUCUC RNA pulldown LC-MS/MS

Project description:The nuclear export of HBV RNAs allows the virus to synthesize its proteins through the translation machinery and replicate its genome through reverse transcription in the cytoplasm. However, the molecular mechanisms underlying this important process remain largely obscure. To illustrate this process, we took advantage of an unbiased HBV RNA-host protein interaction screen using a quantitative proteomics approach and identified embryonic lethal, abnormal vision, Drosophila-like 1 (ELAVL1) as a viral RNA binding partner. RNA scope and subcellular mRNA assays indicated that genetic and pharmaceutic inhibition of ELAVL1 inhibits HBV RNA nuclear export and suppresses viral replication in cell cultures. The observations of an HBV replication mouse model with ELAVL1 displayed similar results. RNA pulldown and RNA electrophoretic mobility shift assays revealed direct interaction between ELAVL1 and HBV pgRNA and confirmed AU-rich elements as the binding sites through site-directed mutagenesis of pgRNA. RNA-immunoprecipitation revealed that HBV RNAs associate with ELAVL1, which in turn binds to acidic leucine-rich nuclear phosphoprotein 32 family member A (ANP32A) and ANP32B. These interactions subsequently recruit CRM1. A nuclear RNase-targeted siRNA screen uncovered RNA exosome-mediated degradation of retardant HBV RNA after ELAVL1 or CRM1 knockdown. Further investigation revealed that ELAVL1 protects pgRNA from degradation. Notably, HBc deletion had no effect on pgRNA-CRM1 interaction and HBV RNA nuclear export. In summary, our work indicates that ELAVL1 functions both in HBV RNA stability and nucleocytoplasmic transport via the CRM1 nuclear export pathway.

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