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Integrative regulatory mapping indicates that the RNA-binding protein HuR (ELAVL1) couples pre-mRNA processing and mRNA stability [sequence data]

ABSTRACT: RNA-binding proteins coordinate the fates of multiple RNAs, but the principles underlying these global interactions remain poorly understood. We elucidated regulatory mechanisms of the RNA-binding protein HuR, by integrating data from diverse high-throughput targeting technologies, specifically PAR-CLIP, RIP-chip, and whole-transcript expression profiling. The number of binding sites per transcript, degree of HuR-association, and degree of HuR-dependent RNA stabilization were positively correlated. Pre-mRNA and mature mRNA containing both intronic and 3' UTR binding sites were more highly stabilized than transcripts with only 3' UTR or only intronic binding sites, suggesting that HuR couples pre-mRNA processing with mature mRNA stability. We also observed HuR-dependent splicing changes and substantial binding of HuR in poly-pyrimidine tracts of pre-mRNAs. Comparison of the spatial patterns surrounding HuR and miRNA binding sites provided functional evidence for HuR-dependent antagonism of proximal miRNA-mediated repression. We conclude that HuR coordinates gene expression outcomes at multiple interconnected steps of RNA processing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE29779 | GEO | 2011/08/19

SECONDARY ACCESSION(S): PRJNA155207

REPOSITORIES: GEO

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Integrative regulatory mapping indicates that the RNA-binding protein HuR (ELAVL1) couples pre-mRNA processing and mRNA stability [sequence data]

Project description:RNA-binding proteins coordinate the fates of multiple RNAs, but the principles underlying these global interactions remain poorly understood. We elucidated regulatory mechanisms of the RNA-binding protein HuR, by integrating data from diverse high-throughput targeting technologies, specifically PAR-CLIP, RIP-chip, and whole-transcript expression profiling. The number of binding sites per transcript, degree of HuR-association, and degree of HuR-dependent RNA stabilization were positively correlated. Pre-mRNA and mature mRNA containing both intronic and 3' UTR binding sites were more highly stabilized than transcripts with only 3' UTR or only intronic binding sites, suggesting that HuR couples pre-mRNA processing with mature mRNA stability. We also observed HuR-dependent splicing changes and substantial binding of HuR in poly-pyrimidine tracts of pre-mRNAs. Comparison of the spatial patterns surrounding HuR and miRNA binding sites provided functional evidence for HuR-dependent antagonism of proximal miRNA-mediated repression. We conclude that HuR coordinates gene expression outcomes at multiple interconnected steps of RNA processing. HuR (ELAVL1) PAR-CLIP

2011-08-19 | E-GEOD-29779 | biostudies-arrayexpress

HuR promotes triglyceride synthesis and intestinal fat absorption

Project description:Triacylglyceride (TAG) synthesis in the small intestine determines the absorption of dietary fat, but the mechanisms underlying are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) promotes TAG synthesis in the small intestine. HuR associates with the 3’UTR of Dgat2 mRNA and the introns 1 of Mgat2 pre-mRNA. Association of HuR with Dgat2 3’UTR stabilizes Dgat2 mRNA, while association of HuR with intron 1 of Mgat2 pre-mRNA promotes the processing of Mgat2 pre-mRNA. Intestinal epithelium-specific HuR knockout reduces the expression of DGAT2 and MGAT2, thereby reducing the dietary fat absorption through TAG synthesis and mitigating high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and obesity. Our findings highlight a critical role of HuR in promoting dietary fat absorption.

2024-04-03 | GSE262777 | GEO

HuR promotes triglyceride synthesis and intestinal fat absorption

2024-01-10 | GSE252591 | GEO

HuR (ELAVL1) RIP-chip and knockdown exon array

2011-08-19 | GSE29778 | GEO

HuR (ELAVL1) RIP-chip and knockdown exon array

Project description:Integrative regulatory mapping indicates that the RNA-binding protein HuR (ELAVL1) couples pre-mRNA processing and mRNA stability In this dataset, we employed two distinct experiments. 1) HuR RIP-chip to identify mRNA targets of HuR. 2) HuR knockdown to identify mRNAs whose expression are dependent on HuR. All 12 samples were normalized with PLIER using Affymetrix power tools. To identify RNA targets of HuR, HuR RIP samples were compared to Mock RIP samples. To identify RNA regulated by HuR, HuR knockdown samples were compared to mock knockdown samples.

2011-08-18 | E-GEOD-29778 | biostudies-arrayexpress

Unstressed HeLa cells and ELAVL1/HuR knock down conditions: polyA RNA-Seq, small RNA-Seq, and PAR-CLIP

2011-06-30 | GSE29943 | GEO

Unstressed HeLa cells and ELAVL1/HuR knock down conditions: polyA RNA-Seq, small RNA-Seq, and PAR-CLIP

Project description:Post-transcriptional gene regulation relies on hundreds of RNA binding proteins (RBPs) but the function of most RBPs is unknown. The human RBP HuR/ELAVL1 is a conserved mRNA stability regulator. We used PAR-CLIP, a method based on RNA-protein crosslinking, to identify transcriptome wide ~26,000 HuR binding sites. These sites were on average highly conserved, enriched for HuR binding motifs and mainly located in 3' untranslated regions. Surprisingly, many sites were intronic, implicating HuR in splicing. Upon HuR knock down, mRNA levels and protein synthesis of thousands of target genes was down regulated, validating functionality. HuR and miRNA binding sites tended to reside nearby but generally did not overlap. Additionally, HuR knock down triggered strong and specific up regulation of miR-7. In summary, we identified thousands of direct and functional HuR targets, found a human miRNA controlled by HuR, and propose a role for HuR in splicing. PolyA mRNA was extracted from anti HuR siRNA treated and mock transfected HeLa cells to identify changes in mRNA expression and splicing. 2x100 paired end sequencing was performed according to the protocol on the Illumina HiSeq. PARCLIP was performed as in Hafner et. Al 2010 but with an antibody against endogenous HuR (3A2, Santa Cruz, sc-5261) in unstressed HeLa cells. We used, independently, 4-thiouridine (4SU) and 6-thioguanosine (6SG) to assess a possible nucleotide bias. As our proteomics measurements required labeling of cells in a special medium we also performed PAR-CLIP on cells grown in SILAC medium. Altogether we performed three PAR-CLIP experiments: 4SU labeling in standard DMEM medium, 4SU labeling in SILAC medium (as a replicate) and 6SG labeling in SILAC medium. Small RNA was extracted from anti HuR siRNA treated and mock transfected HeLa cells to identify changes in mRNA expression. Sequencing was performed on Illumina GAII using the standard sRNA 36cycle protocol.

2011-06-29 | E-GEOD-29943 | biostudies-arrayexpress

Loss of CPSF6 causes developmental disease via bimodal changes in polyadenylation site usage and protein expression [Zebrafish]

Project description:Most pre-messenger RNA (pre-mRNA) undergo extensive processing to create distinct transcripts from the same gene. One of these processes, alternative polyadenylation, involves over twenty proteins to bind and cleave the pre-mRNA at poly(A) sites that can lie within the 3' UTR, introns, or exons; this can modulate protein function, but the effect of choosing a site internal to the gene vs. within the 3' UTR remains unclear. Here we show that reduced expression of CPSF6, one of the proteins involved in site selection, derails development in both humans and zebrafish by causing a bidirectional shift in poly(A) site usage. CPSF6 insufficiency favors the use of intronic poly(A) sites in neuronal genes, reducing mRNA and protein abundance, but promotes 3' UTR site usage in cardiovascular and skeletal genes, upregulating mRNA and protein.These data thus provides a long-sought link between APA and gene expression and shows that poly(A) site selection influences development.

2023-01-15 | GSE206558 | GEO

Loss of CPSF6 causes developmental disease via bimodal changes in polyadenylation site usage and protein expression [Human]

Project description:Most pre-messenger RNA (pre-mRNA) undergo extensive processing to create distinct transcripts from the same gene. One of these processes, alternative polyadenylation, involves over twenty proteins to bind and cleave the pre-mRNA at poly(A) sites that can lie within the 3' UTR, introns, or exons; this can modulate protein function, but the effect of choosing a site internal to the gene vs. within the 3' UTR remains unclear. Here we show that reduced expression of CPSF6, one of the proteins involved in site selection, derails development in both humans and zebrafish by causing a bidirectional shift in poly(A) site usage. CPSF6 insufficiency favors the use of intronic poly(A) sites in neuronal genes, reducing mRNA and protein abundance, but promotes 3' UTR site usage in cardiovascular and skeletal genes, upregulating mRNA and protein.These data thus provide a long-sought link between APA and gene expression and shows that poly(A) site selection influences development.

2023-01-15 | GSE206557 | GEO

Alternative polyadenylation alters protein dosage by switching between intronic and 3' UTR sites

Project description:Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' UTR, introns, or exons. Most studies focus on APA within the 3' UTR, but here we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3' UTR APA and are upregulated. This suggests that, in healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.

2022-11-21 | MSV000090759 | MassIVE

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