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Doxorubicin resistance involves modulation of interferon signaling, transcriptional bursting, and gene co-expression patterns of U-ISGF3-related genes

ABSTRACT: Doxorubicin resistance involves modulation of interferon signaling, transcriptional bursting, and gene co-expression patterns of U-ISGF3-related genes

PROVIDER: PRJNA1150261 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30316867.fastq.gz	Fastqsanger.gz
	SRR30316868.fastq.gz	Fastqsanger.gz
	SRR30316869.fastq.gz	Fastqsanger.gz
	SRR30316870.fastq.gz	Fastqsanger.gz
	SRR30316871.fastq.gz	Fastqsanger.gz

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Doxorubicin resistance involves modulation of interferon signaling, transcriptional bursting, and gene co-expression patterns of U-ISGF3-related genes

Project description:we investigate the transcriptomic alterations induced by doxorubicin (DOX), a commonly used chemotherapeutic agent, in human colon cancer cells. Using single-cell RNA sequencing, we identified distinct cell populations and their transcriptional profiles following subtoxic dose DOX treatment, revealing cell clusters characterized by differential expression of genes involved in cell cycle regulation and interferon (IFN) signaling. We observed that expression of JAK/STAT pathway genes, activated by IFNs, did not correlate with expression of senescence markers. In contrast, DOX-persisting proliferating cells exhibited upregulation of genes induced by the unphosphorylated form of ISGF3 (U‐ISGF3) transcription factor. Further analysis revealed that U‐ISGF3 drives the expression of target genes by modulating the number of mRNA produced per transcriptional burst, potentially contributing to chemoresistance. Importantly, we found high upregulation of HSH2D, a poor prognostic marker, in doxorubicin-resistant U-ISGF3-dependent cells. Moreover, analysis of gene co-expression networks demonstrated that the altered network in DOX-treated cells, rather than individual gene expression levels, may dictate cancer cell fate after chemotherapy.

2024-10-09 | GSE275330 | GEO

Doxorubicin resistance involves modulation of interferon signaling, transcriptional bursting, and gene co-expression patterns of U-ISGF3-related genes.

Project description:Chemotherapy, although effective in treating cancer, can induce various cellular responses, including senescence and drug resistance. Here, we investigate the transcriptomic alterations induced by doxorubicin (DOX), a commonly used chemotherapeutic agent, in human colon cancer cells. Using single-cell RNA sequencing, we identified distinct cell populations and their transcriptional profiles following subtoxic DOX treatment, revealing cell clusters characterized by differential expression of genes involved in cell cycle regulation and interferon (IFN) signaling. DOX-persisting proliferating cells exhibited upregulation of genes reported to be linked to the unphosphorylated form of ISGF3 (U-ISGF3) transcription factor. Furthermore, we found that HSH2D, a poor prognostic marker, was highly upregulated in doxorubicin-surviving proliferative cells, and its expression was correlated with U-ISGF3-related genes. Analysis of transcription kinetics via mathematical modeling revealed that the number of mRNA molecules produced per transcriptional burst was increased for U-ISGF3-related genes. We also observed altered gene co-expression patterns of U-ISGF3-related genes and others upon DOX treatment, which potentially contributes to chemoresistance of DOX-surviving proliferative cells and may influence cancer cell fate after chemotherapy. Our findings highlight U-ISGF3-related genes and the JAK/STAT pathway as potential therapeutic targets for overcoming chemoresistance in colon cancer.

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Topoisomerase II inhibition involves characteristic chromosomal expression patterns: Doxorubicin study

Project description:A variety of important anticancer drugs kill cells by increasing cellular levels of topoisomerase II-DNA cleavage complex. The anthracycline anticancer drug doxorubicin forms a stable ternary complex with DNA and topoisomerase IIa, thereby inhibiting the normal function of the enzyme. In this study we found genes regulated by doxorubicin - induced and repressed - to be located much closer to each other than genes distributed randomly all over the genome (< 100 kbp). Keywords: Doxorubicin-treated human hepatocytes versus non-treated human hepatocytes

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Regulation of stochastic gene bursting by chromatin-independent acetylation

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Genome-wide CRISPR library screening to identify genes involved in the regulation of the kinetic properties of transcriptional bursting

Project description:Cell-to-cell heterogeneity in gene expression can even be observed in the same type of cells, present in a similar environment. Transcriptional bursting is thought to be one of contributing factors to the heterogeneity, but it remains elusive how the kinetic properties of transcriptional bursting (e.g. burst size, burst frequency, and noise induced by transcriptional bursting) are regulated in mammalian cells. To unbiasedly identify genes regulating the kinetic properties of transcriptional bursting, we performed large-scale CRISPR/-Cas9 based screening and functional analysis, and found that Akt/MAPK signaling pathways are involved in the regulation of the kinetic properties of transcriptional bursting.

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Long noncoding RNA-dependent control of Myc transcriptional bursting [HiC]

Project description:Genes are transcribed in short periods of activity, called bursts. Bursts are initiated by enhancer-promoter contacts and dynamically controlled by the levels of enhancer- and promoter-produced RNAs through a negative feedback mechanism. Here, by direct visualization of nascent transcripts, we show that chromatin-associated long noncoding RNAs (lncRNAs) contribute to the regulation of transcriptional bursting. We find that production of Pvt1 raises the baseline of RNA concentration in the locus of the Myc proto-oncogene and acts locally and in a dose-dependent manner to decrease the duration of Myc bursting. Premature termination of Pvt1 led to higher Myc expression and transcriptional activities, resulting in increased cellular proliferation and advanced tumor development in autochthonous models of lung cancer. These findings point to a critical lncRNA-mediated mechanism for Myc regulation and suggest a potentially widespread role for lncRNAs in fine-tuning gene expression through local control of transcriptional bursting.

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Transcription profiling of human hepatocytes treated with doxorubicin and Trovafloxacin, super-series of E-GEOD-11940 and E-GEOD-11941

Project description:This SuperSeries is composed of the following subset Series:; GSE11940: Topoisomerase II inhibition involves characteristic chromosomal expression patterns: Doxorubicin study; GSE11941: Topoisomerase II inhibition involves characteristic chromosomal expression patterns: Trovafloxacin study Experiment Overall Design: Refer to individual Series

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