RNA-seq of dTAG-NUDT21 HCT116 cells treated with DMSO+JTE-607 or dTAGV1+JTE-607.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE306466 | GEO | 2025/09/08
REPOSITORIES: GEO
Similar Datasets
Project description:To assess the impact of CPA inhibition by JTE-607 on intra-cell-line transcriptomic heterogeneity, we profiled two lung cancer cell lines treated with DMSO or JTE-607 by 3' tag-based single-cell RNA-seq with 10x Chromium. For data analysis, we performed transcriptome quantification at the PAS-based transcript level to generate a PAS-by-cell count matrix, and then investigate the effect of JTE-607 treatment on PAS usage pattern and cellular states.
2025-01-14 | GSE286399 | GEO
Project description:To investigate the function of NUDT21 in the regulation of progression of colorectal cancer, we established HCT116 cell line in which each target gene has been knocked down by shRNA. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different cells at two time points.
2024-01-01 | GSE223415 | GEO
Project description:Effect of depletion of NUDT21 on gene expression in HCT116
| PRJNA926109 | ENA
Project description:JTE-607 is a small molecule compound with anti-inflammation and anti-cancer activities. Upon entering the cell, it is hydrolyzed to Compound 2, which directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-mRNA 3' processing. Although CPSF73 is universally required for mRNA 3' end formation, we have unexpectedly found that Compound 2-mediated inhibition of pre-mRNA 3' processing is sequence-specific and that the sequences flanking the cleavage site (CS) are a major determinant for drug sensitivity. By using massively parallel in vitro assays, we have measured the Compound 2 sensitivities of over 260,000 sequence variants and identified key sequence features that determine drug sensitivity. A machine learning model trained on these data can predict the impact of JTE-607 on poly(A) site (PAS) selection and transcription termination genome-wide. We propose a biochemical model in which CPSF73 and other mRNA 3' processing factors bind to RNA of the CS region in a sequence-specific manner and the affinity of such interaction determines the Compound 2 sensitivity of a PAS. Together, our study not only characterized the mechanism of action of a compound with clinical implications, but also revealed a previously unknown sequence-specificity of the mRNA 3' processing machinery.
2023-07-22 | GSE218977 | GEO
Project description:Cleavage and polyadenylation (CPA) defines the 3’ end of almost all eukaryotic mRNAs. CPA inhibition, or CPAi, leads to transcriptional readthrough. Here, we show that the CPSF-73 inhibitor JTE-607 globally perturbs gene expression, especially for those with a high GC content and located in high gene density regions. Based on regulated alternative polyadenylation (APA) events, we found that more frequently used CPA sites are inhibited by JTE-607 to a greater extent. Consistently, cells with elevated CPA activities, as indicated by preferential usage of proximal APA sites, display greater transcriptional readthrough and gene expression disturbance upon JTE-607 treatment. Remarkably, overexpression of the core CPA factor FIP1 enhances global CPA activity in the cell and leads to greater JTE-607 sensitivity. Taken together, our data indicate that CPAi selectively impacts genes based on their genomic features and the CPA activity of a cell is a key determinant of sensitivity to CPAi.
2023-06-07 | GSE218545 | GEO
Project description:Cleavage and polyadenylation (CPA) defines the 3’ end of almost all eukaryotic mRNAs. CPA inhibition, or CPAi, leads to transcriptional readthrough. Here, we show that the CPSF-73 inhibitor JTE-607 globally perturbs gene expression, especially for those with a high GC content and located in high gene density regions. Based on regulated alternative polyadenylation (APA) events, we found that more frequently used CPA sites are inhibited by JTE-607 to a greater extent. Consistently, cells with elevated CPA activities, as indicated by preferential usage of proximal APA sites, display greater transcriptional readthrough and gene expression disturbance upon JTE-607 treatment. Remarkably, overexpression of the core CPA factor FIP1 enhances global CPA activity in the cell and leads to greater JTE-607 sensitivity. Taken together, our data indicate that CPAi selectively impacts genes based on their genomic features and the CPA activity of a cell is a key determinant of sensitivity to CPAi.
2023-06-07 | GSE231527 | GEO
Project description:Cleavage and polyadenylation (CPA) defines the 3’ end of almost all eukaryotic mRNAs. CPA inhibition, or CPAi, leads to transcriptional readthrough. Here, we show that the CPSF-73 inhibitor JTE-607 globally perturbs gene expression, especially for those with a high GC content and located in high gene density regions. Based on regulated alternative polyadenylation (APA) events, we found that more frequently used CPA sites are inhibited by JTE-607 to a greater extent. Consistently, cells with elevated CPA activities, as indicated by preferential usage of proximal APA sites, display greater transcriptional readthrough and gene expression disturbance upon JTE-607 treatment. Remarkably, overexpression of the core CPA factor FIP1 enhances global CPA activity in the cell and leads to greater JTE-607 sensitivity. Taken together, our data indicate that CPAi selectively impacts genes based on their genomic features and the CPA activity of a cell is a key determinant of sensitivity to CPAi.
2023-06-07 | GSE218555 | GEO
Project description:HCC is the third leading cause of cancer-related deaths worldwide. However, the molecular mechanisms underlying the progression of HCC is still largely elusive. NUDT21 (CFIm25) is an important mediator of 3′ UTR APA and demonstrates a causal relationship between alternative polyadenylation and cancer cell proliferation. Although the function of NUDT21 has been explored in glioblastoma tumor, the functional significance of NUDT21 in solid tumors is not well understood. In this study, we observed that NUDT21 is suppressed in human HCC tissues, compared to adjacent noncancerous tissues. In addition we found that the HCC patients with suppressed NUDT21 are statistically associated with poor outcomes. These observations suggest NUDT21 possibly functions as tumor suppressor in hepatocellular carcinoma (HCC).
2018-01-25 | E-MTAB-6368 | biostudies-arrayexpress
Project description:Alternative polyadenylation (APA) serves as a critical mechanism for shaping transcriptome diversity and modulating cancer therapeutic resistance. While lactate is a well-established metabolic signal in cancer progression, its role in APA regulation remains unclear. Here, we demonstrate that L-lactate-induced lactylation of NUDT21 drives transcriptomic reprogramming through APA modulation. NUDT21 lactylation enhances its interaction with CPSF6, facilitating CFIm complex formation and inducing 3′ untranslated region (UTR) lengthening of FDX1. Extension of the FDX1 3′ UTR attenuates its protein output, thereby conferring resistance to cuproptosis in esophageal squamous cell carcinoma (ESCC). Furthermore, we identify AARS1 as the lactylation “writer” catalyzing NUDT21 K23 lactylation, and HDAC2 as its enzymatic “eraser”. Clinically, elevated LDHA and NUDT21 levels correlate with reduced FDX1 expression and worse prognosis in ESCC patients. Notably, combined targeting of the lactate-NUDT21-FDX1-cuproptosis axis with the clinical LDHA inhibitor stiripentol and the copper ionophore elesclomol synergistically suppressed tumor growth. Collectively, our work identifies lactylated NUDT21 as a critical factor linking cellular metabolism to APA and proposes a promising therapeutic strategy for ESCC treatment.
2025-05-12 | GSE284372 | GEO
Project description:We identified LAMC1 as a critical NUDT21 target involved in several core glioma-driving signaling pathways. qRT-PCR analysis confirmed that NUDT21-knockdown in GBM cells resulted in the preferred usage of the proximal C/PAS of LAMC1. Furthermore, functional studies revealed that NUDT21-knockdown-induced 3’UTR shortening of LAMC1 was sufficient to induce translational gain, as LAMC1 was upregulated in these cells compared to their respective controls. Additionally, we demonstrated that primary glial cells recapitulated this phenomenon. We also further dissected the miRNA-mediated mechanism by which LAMC1 expression was regulated by showing that NUDT21 knockdown in glioma cells directed the 3’UTR shortening of LAMC1, removing binding sites for miR-124/506 and consequently inducing LAMC1 expression. Remarkably, we reported that the knockdown of NUDT21 significantly promoted GBM cell migration and that co-depletion of LAMC1 and NUDT21 abrogated this effect. Lastly, we observed that LAMC1 3’UTR shortening predicted poor prognosis of low- and high-grade glioma patients from The Cancer Genome Atlas.
2024-05-01 | GSE230769 | GEO