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Isoform Usage as a Distinct Regulatory Layer Driving Nutrient-Responsive Metabolic Adaptation (Monkey-Pacbio)

ABSTRACT: This study outlines the landscape of isoform usage modulations across major metabolic organs in both mice and monkeys, spanning diverse metabolic states. Our in-depth analysis identify numerous isoform-usage events, intricately influenced by nutrient challenges and largely independent of gene expression regulation. When analysing splicing factor-binding motifs in nutrient-regulated events, HuR emerges as the predominant orchestrator of the isoform network in adipocytes.

ORGANISM(S): Macaca fascicularis

PROVIDER: GSE248832 | GEO | 2025/02/03

REPOSITORIES: GEO

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Isoform Usage as a Distinct Regulatory Layer Driving Nutrient-Responsive Metabolic Adaptation (RIP-seq)

Project description:This study outlines the landscape of isoform usage modulations across major metabolic organs in both mice and monkeys, spanning diverse metabolic states. Our in-depth analysis identify numerous isoform-usage events, intricately influenced by nutrient challenges and largely independent of gene expression regulation. When analysing splicing factor-binding motifs in nutrient-regulated events, HuR emerges as the predominant orchestrator of the isoform network in adipocytes.

2025-02-03 | GSE248965 | GEO

Isoform Usage as a Distinct Regulatory Layer Driving Nutrient-Responsive Metabolic Adaptation (RNA-seq)

2025-02-03 | GSE248964 | GEO

Isoform Usage as a Distinct Regulatory Layer Driving Nutrient-Responsive Metabolic Adaptation

Project description:Transcriptome modulation is essential for metabolic adaptation to nutrient environments. However, the role of isoform usage, a crucial transcriptome component, is not yet fully understood. This study outlines the landscape of isoform usage modulations across major metabolic organs in both mice and monkeys, spanning diverse metabolic states. Our in-depth analysis identifies numerous isoform-usage events, intricately influenced by nutrient challenges and largely independent of gene expression regulation. Comparative analyses of mice and monkeys highlight hundreds of conserved isoform events that exhibit consistent responses to nutrient challenges across species and correlate with human metabolic traits. When analysing splicing factor-binding motifs in nutrient-regulated events, HuR emerges as the predominant orchestrator of the isoform network in adipocytes, which is validated using an adipose tissue-specific knockout and an Ap2-promoter-driven transgenic mouse model. In summary, our results offer a comprehensive perspective on isoform usage in metabolic regulation, setting a platform for future functional inquiries.

2025-02-03 | GSE248966 | GEO

Isoform Usage as a Distinct Regulatory Layer Driving Nutrient-Responsive Metabolic Adaptation (Monkey-Pacbio)

Project description:Isoform Usage as a Distinct Regulatory Layer Driving Nutrient-Responsive Metabolic Adaptation (Monkey-Pacbio)

| PRJNA1046080 | ENA

mRNA stability factor HuR promotes immune evasion in pancreatic ductal adenocarcinoma [RIP-seq]

Project description:The limited infiltration of tumor-specific T cells into the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) is hypothesized to limit immunotherapy responses. The RNA-binding protein, HuR (ELAVL1), is over-abundant in PDAC, and its expression negatively correlates with T cell infiltration. In the immunocompetent Kras-p53-Cre (KPC) model, we found HuR depletion impairs tumor growth. To investigate the impact of the immune cells on tumor growth, we analyzed the infiltrated immune population in tumors and found that HuR-depleted tumors had increased T cell infiltration and activation. Mechanistically, HuR mediated stabilization of mTOR pathway and enhanced PDAC nutrient consumption, which impaired local T-cell antitumor function. We found that HuR suppression of antitumor immunity has profound consequences, as HuR-deficient tumors are sensitive to immune checkpoint blockade, while isogenic, wildtype tumors are resistant. These findings describe a novel role of HuR in PDAC facilitating tumor immune suppression in the PDAC TME by inhibiting T cell infiltration and function.

2025-02-05 | GSE287349 | GEO

mRNA stability factor HuR promotes immune evasion in pancreatic ductal adenocarcinoma

2025-02-05 | GSE287307 | GEO

Pancreatic cancer-intrinsic HuR regulates the pro-tumorigenic properties of extracellular vesicles

Project description:Pancreatic ductal adenocarcinoma (PDAC) tumors contain chaotic vasculature that limits immune surveillance and promotes early events in the metastatic cascade. However, current antiangiogenic therapies have failed in PDAC, and it remains important to uncover mechanisms by which cancer cells signal to endothelial cells to increase angiogenesis. The tumor-intrinsic RNA-binding protein HuR (ELAVL1) plays an important role re-shaping the tumor microenvironment (TME) by regulating the stability and translation of cytokine encoding transcripts. PDAC-intrinsic HuR influenced endothelial cell function in the TME via extracellular vesicle (EV) signaling, an underexplored signaling axis in tumor progression. HuR knockout (KO) tumors had impaired growth in an immunocompetent mouse model, and that administering purified wildtype (WT) EVs increased tumor growth. Further, isobaric-labeling quantitative proteomics showed that PDAC EVs contained HuR-dependent cargos relating to endothelial cell function and angiogenesis. Treatment of endothelial cells with HuR WT EVs strongly increased the expression of genes involved in barrier function, endothelial cell development, and directly increased their migratory and tube forming functions. In an immunocompetent orthotopic mouse model of PDAC, HuR increased endothelial cell presence and sprouting, while decreasing ICAM-1 expression. When utilizing the PalmGRET genetic EV reporter, decreased ICAM-1 within WT tumors occurred in endothelial cells that had imported PDAC EVs, suggesting signaling that directly modulates endothelial cell behavior in vivo. Collectively, our data reveal a new role of HuR in EV signaling to endothelial cells, promoting angiogenesis while restricting endothelial cell leukocyte trafficking behavior.

2025-08-09 | PXD059674 | Pride

Adipose tissue protein kinase D (PKD): regulation of signalling networks and its effect on metabolism

Project description:The protein kinase D (PKD) family of three highly homologous isoforms (PKD1, PKD2, and PKD3) are implicated as nutrient sensing signalling kinases that regulate the response of adipose and other tissues to the nutrient environment. However, the physiological role of adipose tissue PKD and the cellular signalling targets downstream of adipose tissue PKD are not well characterised. Here we employed phosphoproteomics to elucidate signalling events downstream of PKD activation in differentiated 3T3-L1 adipocytes using a triple isoform siRNA knockdown model. This identified PKD-regulated pathways including insulin and cAMP signalling, which control metabolic responses in adipose tissue.

2025-05-27 | PXD056412 | Pride

Isoform-resolved transcriptome of the human preimplantation embryo [PacBio]

Project description:Human preimplantation development is a complex process involving extensive remodeling of gene expression. However, the preimplantation embryo transcriptome has only been annotated using short-read sequencing, which fails to capture full-length mRNAs and associated isoform diversity. We present a novel human embryo transcriptome using integrated long- and short-read RNA sequencing data. Our analysis reveals a total of 110,212 novel isoforms transcribed from known genes containing either a novel combination of known splice sites or at least one novel splice site, and 17,964 isoforms transcribed from completely novel genes located either in antisense direction of known genes or in intergenic space.

2023-09-26 | GSE190547 | GEO

Rip-Chip profiling of HnRNP A1 nuclear complexes in HuR WT and HuR KO cells

Project description:Post-transcriptional regulatory networks are dependent on the interplay of many RNA-binding proteins having a major role in mRNA processing events in mammals. We have been interested in the concerted action of the two RNA-binding proteins hnRNP A1 and HuR, both stable components of immunoselected hnRNP complexes and having a major nuclear localization. Specifically, we present here the application of the RNA-immunoprecipitation (RIP)-Chip technology to identify a population of nuclear transcripts associated with hnRNP A1-RNPs as isolated from the nuclear extract of either HuR WT or HuR-depleted (KO) mouse embryonic fibroblast (MEF) cells. The outcome of this analysis was a list of target genes regulated via HuR for their association (either increased or reduced) with the nuclear hnRNP A1-RNP complexes. Real time PCR analysis was applied to validate a selected number of nuclear mRNA transcripts, as well as to identify pre-spliced transcripts (in addition to their mature mRNA counterpart) within the isolated nuclear hnRNP A1-RNPs. The differentially enriched mRNAs were found to belong to GO categories relevant to biological processes anticipated for hnRNP A1 and HuR (such as transport, transcription, translation, apoptosis and cell cycle) indicative of their concerted function in mRNA metabolism. Ribonucleoprotein Immunoprecipitation (RIP) using hnRNP A1 specific antibody was performed in nuclear extracts from HuR WT and HuR KO Mouse Embryonic Fibroblasts (MEFs). RNA isolated from these IPs together with nuclear RNA from the two cell types, was subjected to microarray analysis. Three biological replicates, representing three independent experiments, are available for each condition except in the case of nuclear RNA isolated from HuR WT MEFs that one replicate didn’t pass the quality control.

2013-11-01 | E-GEOD-49225 | biostudies-arrayexpress

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