Ontology highlight
ABSTRACT:
PROVIDER: PRJNA853906 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19894765.fastq.gz | Fastqsanger.gz | |||
| SRR19894766.fastq.gz | Fastqsanger.gz | |||
| SRR19894767.fastq.gz | Fastqsanger.gz | |||
| SRR19894768.fastq.gz | Fastqsanger.gz | |||
| SRR19894769.fastq.gz | Fastqsanger.gz |
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Project description:NOP2/Sun RNA methyltransferase family member 2 (NSUN2) catalyzes 5-methylcytosine (m5C) modifications in tRNA, rRNA, and mRNA, playing critical roles in various malignancies. However, its expression and functional relevance in B-acute lymphoblastic leukemia (B-ALL) remain largely undefined. Lineage-negative progenitor cells from Nsun2 knockout (Δ/Δ) and wild-type (fl/fl) mice were used to generate BCR-ABL (P190)-driven murine B-ALL model. Furthermore, RNA sequencing (RNA-seq) was performed to identify NSUN2 targets. Here, we found that NSUN2 expression was significantly higher in bone marrow (BM) cells from B-ALL patients than normal controls (NCs). Knockdown of NSUN2 reduced m5C amounts, induced apoptosis and ferroptosis in B-ALL cells. Moreover, Nsun2 knockout significantly suppressed the leukemic burden and extended the OS in murine B-ALL model in vivo. RNA-seq and subsequent studies identified ferritin heavy chain 1 (FTH1) as a downstream target of NSUN2. Mechanistically, NSUN2 knockdown reduced m5C modifications on 3'UTR of FTH1 mRNA, impairing its stability and reducing FTH1 expression. Overexpression of wild-type (WT) NSUN2, but not its mutants, blocked NSUN2 knockdown-induced cytotoxic effects, indicating that NSUN2 enhances leukemogenesis in an m5C-dependent manner. In addition, NSUN2 facilitated global protein synthesis and ribosome biogenesis by enhancing fibrillarin (FBL) translation efficiency. In contrast, Nsun2 depletion was dispensable for hematopoiesis and exerted minimal impact on ferroptosis and protein synthesis in murine pre-B (B220+) cells, suggesting selective leukemic dependency. Our results demonstrate that NSUN2 facilitates leukemogenesis by increasing FTH1 expression and enhancing FBL-mediated ribosome biogenesis in an m5C-dependent manner. Targeting NSUN2 might provide a promising therapeutic strategy for B-ALL.
2025-09-09 | GSE299607 | GEO
Project description:NOP2/Sun RNA methyltransferase family member 2 (NSUN2) catalyzes 5-methylcytosine (m5C) modifications in tRNA, rRNA, and mRNA, playing critical roles in various malignancies. However, its expression and functional relevance in B-acute lymphoblastic leukemia (B-ALL) remain largely undefined. Lineage-negative progenitor cells from Nsun2 knockout (Δ/Δ) and wild-type (fl/fl) mice were used to generate BCR-ABL (P190)-driven murine B-ALL model. Furthermore, RNA sequencing (RNA-seq) was performed to identify NSUN2 targets. Here, we found that NSUN2 expression was significantly higher in bone marrow (BM) cells from B-ALL patients than normal controls (NCs). Knockdown of NSUN2 reduced m5C amounts, induced apoptosis and ferroptosis in B-ALL cells. Moreover, Nsun2 knockout significantly suppressed the leukemic burden and extended the OS in murine B-ALL model in vivo. RNA-seq and subsequent studies identified ferritin heavy chain 1 (FTH1) as a downstream target of NSUN2. Mechanistically, NSUN2 knockdown reduced m5C modifications on 3'UTR of FTH1 mRNA, impairing its stability and reducing FTH1 expression. Overexpression of wild-type (WT) NSUN2, but not its mutants, blocked NSUN2 knockdown-induced cytotoxic effects, indicating that NSUN2 enhances leukemogenesis in an m5C-dependent manner. In addition, NSUN2 facilitated global protein synthesis and ribosome biogenesis by enhancing fibrillarin (FBL) translation efficiency. In contrast, Nsun2 depletion was dispensable for hematopoiesis and exerted minimal impact on ferroptosis and protein synthesis in murine pre-B (B220+) cells, suggesting selective leukemic dependency. Our results demonstrate that NSUN2 facilitates leukemogenesis by increasing FTH1 expression and enhancing FBL-mediated ribosome biogenesis in an m5C-dependent manner. Targeting NSUN2 might provide a promising therapeutic strategy for B-ALL.
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Project description:Ribosome profiling of MDA-MB-231 cells treated with Silvestrol to monitor transcriptome wide, eIF4A-dependent changes in translation efficiency Translation efficiency (TE) of mRNAs dervied from ribosome footprints was monitored in the presence or absence of 25 nM Silvestrol, an inhibitor of eukaryotic translation initiation factor 4A (eIF4A). Transcripts with reduced TE in the presence of Silvestrol were compare to transcripts with reduced TE in the presence of INK128, a catalytic mTOR inhbitor.
2014-09-13 | E-GEOD-61375 | biostudies-arrayexpress
Project description:Purpose: Ribosome profiling has revolutionized systems-based analysis and which produces a âglobal snapshotâ of all the ribosomes translationally active in a cell at a particular moment. The goals of this study are to first apply ribosome profiling to in vivo samples for the first time and in particular to stem cells and tumours and second to determine which mRNAs are being actively translated in these particular situations. Although much is known about gene expression regulation, little is known about how protein translation regulation can affect stem cell differentiation and tumour progression. Methods: several replicates of ribosome and mRNA profiles of wild-type (WT) and NSun2 -/- mouse skin squamous tumours were generated by deep sequencing, using Illumina HiSeq platform. Results: Our analyses reveal that activation of stress response pathways in vivo drives both a global reduction of protein synthesis and altered translation of specific mRNAs that together promote stem cell functions and tumourigenesis. Ribosome profiles of wild-type (WT) and NSun2 -/- mouse skin squamous tumours
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Project description:Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as "translational offsetting" of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5'UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modifying enzymes and thereby controls levels of U34-modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.
2019-09-24 | GSE120914 | GEO
Project description:Plasmodium falciparum, the deadliest malaria-causing parasite, challenges eradication efforts due to drug resistance. To date, mRNA translation remains an unexplored therapeutic target. Most mRNAs contain unusually long 5’UTR and multiple upstream AUGs. How the parasite overcomes scanning distance and uORF constraints is unknown. Using Ribo-seq, TIS-seq, and long-read data, we mapped translation initiation sites, determined translation efficiency, and re-annotated the 5’UTRs. We identified actively translated uORFs in 81% of mRNAs, predominantly initiated by unspecified AUG, while inactive uORFs are enriched with inhibitory AUG contexts. Notably, initiation within CDS through leaky scanning is also highly prevalent. Surprisingly, mRNAs with long 5’UTR and active uORFs exhibit higher translation efficiency compared to those lacking uORFs. This is facilitated by a specific spacing of active uORFs and peptide length, optimizing scanning distance, ribosome density, and reinitiation. Remarkably, one-hour exposure to the eIF1-eIF4G1 inhibitor i14G1-12 reduced parasite cell viability and caused translational repression by enhancing leaky scanning and disturbing the unique arrangement of uORFs. Collectively, our findings uncovered the unusual translation regulatory features of P. falciparum and highlighted the therapeutic potential of targeting these mechanisms
2025-11-24 | GSE286083 | GEO
Project description:Multiple epitranscriptomic maps of the RNA modification 5-methylcytosine (m5C) have been prepared, often diverging markedly from each other in terms of site abundance and identity. Differences in detection methods, data depth and analysis pipelines, but also biological factors underly much of this disparity. To address this, we re-analysed available datasets from five human cell lines and seven tissues, generated by the prevailing bisulfite RNA sequencing method, with a coherent m5C site calling pipeline. We used the resulting union list of 6,393 m5C sites called across the broader transcriptome to study site distribution, enzymology, interaction with RNA-binding proteins and molecular function. We confirmed prior observations such as predominance of m5C sites within mRNA exons, enrichment around start codons, and that the tRNA:m5C methyltransferases (MTases) NSUN2 and 6 are the main m5C ‘writers’ for mRNAs. Each NSUN enzyme recognises mRNA features that strongly resemble their respective canonical substrates. Assessing proximity between mRNA m5C sites and footprints of RNA-binding proteins reconfirmed the mRNA export factor ALYREF as an m5C ‘reader’ and identified new candidates for functional interactions, including the RNA helicases DDX3X, involved in mRNA translation, and UPF1, an mRNA decay factor. Experiments in HeLa cells lacking NSUN2 showed that this affected both, steady-state level and UPF1-binding to target mRNAs. Our studies emphasise the emerging diversity of both, m5C writers and readers, affecting mRNA function.
2024-07-04 | GSE252369 | GEO
Project description:Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as "translational offsetting" of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5'UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modifying enzymes and thereby controls levels of U34-modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.
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Project description:Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as "translational offsetting" of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5'UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modifying enzymes and thereby controls levels of U34-modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.
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Project description:Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as "translational offsetting" of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5'UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modifying enzymes and thereby controls levels of U34-modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.
2019-09-24 | GSE120535 | GEO