Expression dynamics of periodic transcripts during cancer cell cycle progression and their correlation with anticancer drug sensitivity
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ABSTRACT:
PROVIDER: PRJNA894098 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22029258_1.fastq.gz | Fastqsanger.gz | |||
| SRR22029258_2.fastq.gz | Fastqsanger.gz | |||
| SRR22029259_1.fastq.gz | Fastqsanger.gz | |||
| SRR22029259_2.fastq.gz | Fastqsanger.gz | |||
| SRR22029260_1.fastq.gz | Fastqsanger.gz |
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Project description:Cell cycle is the center of cellular activities and is orchestrated by complex regulatory mechanisms, among which transcriptional regulation is one of the most important parts. Alternative splicing dramatically expands the regulatory network by producing transcript isoforms of genes to exquisitely control the cell cycle. However, the patterns of transcript isoform expression in the cell cycle are unclear. Therapies targeting cell cycle checkpoints are commonly used as anticancer therapies, but none of them were designed and have been evaluated at alternative splicing transcripts level. To explore alternative splicing patterns during cell cycle progression, we performed sequential transcriptomic assays following cell cycle synchronization in breast cancer MDA-MB-231 cell lines, used flow cytometry and reference cell cycle transcripts to confirm the cell cycle phases of samples.
2022-12-28 | GSE216497 | GEO
Project description:BackgroundThe cell cycle is at the center of cellular activities and is orchestrated by complex regulatory mechanisms, among which transcriptional regulation is one of the most important components. Alternative splicing dramatically expands the regulatory network by producing transcript isoforms of genes to exquisitely control the cell cycle. However, the patterns of transcript isoform expression in the cell cycle are unclear. Therapies targeting cell cycle checkpoints are commonly used as anticancer therapies, but none of them have been designed or evaluated at the alternative splicing transcript level. The utility of these transcripts as markers of cell cycle-related drug sensitivity is still unknown, and studies on the expression patterns of cell cycle-targeting drug-related transcripts are also rare.MethodsTo explore alternative splicing patterns during cell cycle progression, we performed sequential transcriptomic assays following cell cycle synchronization in colon cancer HCT116 and breast cancer MDA-MB-231 cell lines, using flow cytometry and reference cell cycle transcripts to confirm the cell cycle phases of samples, and we developed a new algorithm to describe the periodic patterns of transcripts fluctuating during the cell cycle. Genomics of Drug Sensitivity in Cancer (GDSC) drug sensitivity datasets and Cancer Cell Line Encyclopedia (CCLE) transcript datasets were used to assess the correlation of genes and their transcript isoforms with drug sensitivity. We identified transcripts associated with typical drugs targeting cell cycle by determining correlation coefficients. Cytotoxicity assays were used to confirm the effect of ENST00000257904 against cyclin dependent kinase 4/6 (CDK4/6) inhibitors. Finally, alternative splicing transcripts associated with mitotic (M) phase arrest were analyzed using an RNA synthesis inhibition assay and transcriptome analysis.ResultsWe established high-resolution transcriptome datasets of synchronized cell cycle samples from colon cancer HCT116 and breast cancer MDA-MB-231 cells. The results of the cell cycle assessment showed that 43,326, 41,578 and 29,244 transcripts were found to be periodically expressed in HeLa, HCT116 and MDA-MB-231 cells, respectively, among which 1280 transcripts showed this expression pattern in all three cancer cell lines. Drug sensitivity assessments showed that a large number of these transcripts displayed a higher correlation with drug sensitivity than their corresponding genes. Cell cycle-related drug screening showed that the level of the CDK4 transcript ENST00000547281 was more significantly associated with the resistance of cells to CDK4/6 inhibitors than the level of the CDK4 reference transcript ENST00000257904. The transcriptional inhibition assay following M phase arrest further confirmed the M-phase-specific expression of the splicing transcripts. Combined with the cell cycle-related drug screening, the results also showed that a set of periodic transcripts, for example, ENST00000314392 (a dolichyl-phosphate mannosyltransferase polypeptide 2 isoform transcript), was more associated with drug sensitivity than the levels of their corresponding gene transcripts.ConclusionsIn summary, we identified a panel of cell cycle-related periodic transcripts and found that the levels of transcripts of drug target genes showed different values for predicting drug sensitivity, providing novel insights into alternative splicing-related drug development and evaluation.
| S-EPMC9762028 | biostudies-literature
Project description:A major impediment to the effective treatment of patients with PDAC (Pancreatic Ductal Adenocarcinoma) is the molecular heterogeneity of the disease, which is reflected in an equally diverse pattern of clinical responses to therapy. We developed an efficient strategy in which PDAC samples from 17 consecutively patients were obtained by EUS-FNA or surgery, their cells maintained as a primary culture and tumors as breathing tumors by xenografting in immunosuppressed mice. For these patients a clinical follow up was obtained. On the breathing tumors we studied the RNA expression profile by an Affymetrix approach. We observed a significant heterogeneity in their RNA expression profile, however, the transcriptome was able to discriminate patients with long- or short-time survival which correspond to moderately- or poorly-differentiated PDAC tumors respectively. Cells allowed us the possibility to analyze their relative sensitivity to several anticancer drugs in vitro by developing a chimiogram, like an antibiogram for microorganisms, with several anticancer drugs for obtaining an individual profile of drug sensitivity and as expected, the response was patient-dependent. Interestingly, using this approach, we also found that the transcriptome analysis could predict the sensitivity to some anticancer drugs of patients with a PDAC. In conclusion, using this approach, we found that the transcriptome analysis could predict the sensitivity to some anticancer drugs and the clinical outcome of patients with a PDAC. PDAC samples from 17 consecutively patients were obtained by Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) or surgery. Consents of informed patients were collected, and the ethics review board of the three centers approved the study. All samples were anonymized and obtained in accordance with institutional review boards. EUS-FNA cells were maintained as a primary culture and tumors as breathing tumors by xenografting in immunosuppressed mice. We characterized 17 PDAC-derived xenografts by duplicate. Total RNA was extracted and hybridized on Human Gene 2.0 (Genechip, Affymetrix) as described previously (Hamidi et al. JCI 122: 2092-2103, 2012).
2015-04-09 | E-GEOD-55513 | biostudies-arrayexpress
Project description:A major impediment to the effective treatment of patients with PDAC (Pancreatic Ductal Adenocarcinoma) is the molecular heterogeneity of the disease, which is reflected in an equally diverse pattern of clinical responses to therapy. We developed an efficient strategy in which PDAC samples from 17 consecutively patients were obtained by EUS-FNA or surgery, their cells maintained as a primary culture and tumors as breathing tumors by xenografting in immunosuppressed mice. For these patients a clinical follow up was obtained. On the breathing tumors we studied the RNA expression profile by an Affymetrix approach. We observed a significant heterogeneity in their RNA expression profile, however, the transcriptome was able to discriminate patients with long- or short-time survival which correspond to moderately- or poorly-differentiated PDAC tumors respectively. Cells allowed us the possibility to analyze their relative sensitivity to several anticancer drugs in vitro by developing a chimiogram, like an antibiogram for microorganisms, with several anticancer drugs for obtaining an individual profile of drug sensitivity and as expected, the response was patient-dependent. Interestingly, using this approach, we also found that the transcriptome analysis could predict the sensitivity to some anticancer drugs of patients with a PDAC. In conclusion, using this approach, we found that the transcriptome analysis could predict the sensitivity to some anticancer drugs and the clinical outcome of patients with a PDAC.
2015-04-09 | GSE55513 | GEO
Project description:Anticancer drug clustering in lung cancer based on gene expression profiles. We performed gene expression analysis in lung cancer cell lines. (used: Affymetrix GeneChip Human Genome U133 Array Set HG-U133A). We also examines the sensitivity of these cell lines to commonly used anti-cancer agents (docetaxel, paclitaxel, gemcitabine, vinorelbine, 5-FU, SN38, cisplatin, and carboplatin) via MTT assay. We related the cytoxic activity of each of these agents to corresponding expression pattern in each of the cell lines using modified NCI program. Keywords: cytotoxicity, lung cancer, anticancer drugs
2006-02-10 | GSE4127 | GEO
Project description:DNA binding anticancer agents cause alteration in chromatin structure and dynamics. Here, we report the dynamic interaction of the DNA intercalator and potential anticancer, plant alkaloid, Sanguinarine (SGR) with chromatin. Association of SGR with different levels of chromatin structure was found to be enthalpydriven. Apart from DNA it binds with comparable affinity to histones and induces chromatin aggregation. The dual binding property of SGR leads to inhibition of core histone modifications. Although, it potently inhibits H3K9 methylation by G9a in vitro, H3K4 and H3R17 methylation are more profoundly inhibited in cells. SGR inhibits histone acetylation both in vitro and in vivo. It does not affect the in vitro transcription from DNA template but significantly represses acetylation dependent chromatin transcription. SGR mediated repression of epigenetic marks and the alteration of chromatin geography, also result in modulation of global gene expression. These data conclusively, show the anticancer DNA binding intercalator as a modulator of chromatin modifications and transcription in the chromatin context.
2009-02-28 | GSE14314 | GEO
Project description:DNA-binding anticancer agents cause alteration in chromatin structure and dynamics. Here, we report the dynamic interaction of the DNA intercalator and potential anticancer, plant alkaloid, sanguinarine (SGR) with chromatin. Association of SGR with different levels of chromatin structure was found to be enthalpy driven. Apart from DNA, it binds with comparable affinity to histones and induces chromatin aggregation. The dual binding property of SGR leads to inhibition of core histone modifications. Although it potently inhibits H3K9 methylation by G9a in vitro, H3K4 and H3R17 methylation are more profoundly inhibited in cells. SGR inhibits histone acetylation both in vitro and in vivo. It does not affect the in vitro transcription from DNA template but significantly represses acetylation-dependent chromatin transcription. SGR mediated repression of epigenetic marks and the alteration of chromatin geography also result in modulation of global gene expression. These data conclusively show that the anticancer DNA-binding intercalator as a modulator of chromatin modifications and transcription in the chromatin context.
2011-09-12 | GSE14777 | GEO
Project description:The eukaryotic cell cycle, driven by both transcriptional and post-translational mechanisms, is the central molecular oscillator underlying tissue growth throughout animals. While genome-wide studies have investigated cell cycle-associated transcription in unicellular systems, global patterns of periodic transcription in multicellular tissues remain largely unexplored. Here we define the cell cycle-associated transcriptome of the developing Drosophila wing epithelium and compare it with that of cultured Drosophila S2 cells, revealing a core set of periodic genes as well as a surprising degree of context-specificity in periodic transcription. We further employ RNAi-mediated phenotypic profiling to define functional requirements for over 300 periodic genes, with a focus on those required for cell proliferation in vivo. Finally, we investigate the role of novel genes required for interkinetic nuclear migration. Combined, these findings provide a global perspective on cell cycle control in vivo, and highlight a critical need to understand the context-specific regulation of cell proliferation.
2014-03-15 | GSE54926 | GEO
Project description:DNA binding anticancer agents cause alteration in chromatin structure and dynamics. Here, we report the dynamic interaction of the DNA intercalator and potential anticancer, plant alkaloid, Sanguinarine (SGR) with chromatin. Association of SGR with different levels of chromatin structure was found to be enthalpydriven. Apart from DNA it binds with comparable affinity to histones and induces chromatin aggregation. The dual binding property of SGR leads to inhibition of core histone modifications. Although, it potently inhibits H3K9 methylation by G9a in vitro, H3K4 and H3R17 methylation are more profoundly inhibited in cells. SGR inhibits histone acetylation both in vitro and in vivo. It does not affect the in vitro transcription from DNA template but significantly represses acetylation dependent chromatin transcription. SGR mediated repression of epigenetic marks and the alteration of chromatin geography, also result in modulation of global gene expression. These data conclusively, show the anticancer DNA binding intercalator as a modulator of chromatin modifications and transcription in the chromatin context. The total RNA was isolated from control and treated cells using TRIZOL (Invitrogen) method. The Micromax direct labeling kit, MPS502 (PerkinElmer) was used to synthesize the labeled cDNA from 70 ug of total RNA and further process the hybridized cDNA on the array. All the steps were carried out according to manufacturerâs instructions (www.perkinelmer.com/lifesciences). The array slides were scanned immediately by PerkinElmer Scan array Gx Microarray scanner. The Scan array software (PerkinElmer) was used for grid wise normalization of array images. Two arrays were used with at least one biological treatment of cells and dye swap experiment were included in the final analysis. . The data was analysed by GeneSpring GX and Biointerpreter software from Genotypic Technology, Bangalore. The differential expression was considered if the Log 2 mean of at least -1 for the down regulated genes and +1 for the upregulated genes. We considered only the genes that were reproducible from both replicates.
2010-05-22 | E-GEOD-14314 | biostudies-arrayexpress
Project description:DNA-binding anticancer agents cause alteration in chromatin structure and dynamics. Here, we report the dynamic interaction of the DNA intercalator and potential anticancer, plant alkaloid, sanguinarine (SGR) with chromatin. Association of SGR with different levels of chromatin structure was found to be enthalpy driven. Apart from DNA, it binds with comparable affinity to histones and induces chromatin aggregation. The dual binding property of SGR leads to inhibition of core histone modifications. Although it potently inhibits H3K9 methylation by G9a in vitro, H3K4 and H3R17 methylation are more profoundly inhibited in cells. SGR inhibits histone acetylation both in vitro and in vivo. It does not affect the in vitro transcription from DNA template but significantly represses acetylation-dependent chromatin transcription. SGR mediated repression of epigenetic marks and the alteration of chromatin geography also result in modulation of global gene expression. These data conclusively show that the anticancer DNA-binding intercalator as a modulator of chromatin modifications and transcription in the chromatin context. The total RNA was isolated from control and treated cells using the TRIzol (Invitrogen) method. The Micromax direct labeling kit, MPS502 (PerkinElmer), was used to synthesize the labeled cDNA from 70 ug of total RNA and further process the hybridized cDNA on the array. All the steps were carried out according to manufacturer’s instructions (www.perkinelmer.com/lifesciences). The array slides were scanned immediately by the PerkinElmer Scan array Gx Microarray scanner. The Scan array software (PerkinElmer) was used for grid wise normalization of array images. Five arrays were used with at least two biological treatments of cells, and dye-swap experiments were included in the final analysis. The data was analysed by GeneSpring GX and Biointerpreter software from Genotypic Technology, Bangalore. The differential expression was considered if the Log 2 mean of at least -1 for the downregulated genes and +1 for the upregulated genes. We considered only the genes that were reproducible from all five replicates.
2011-09-11 | E-GEOD-14777 | biostudies-arrayexpress