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| Status |
Public on Jul 18, 2023 |
| Title |
Circadian time-series RNA-sequencing of SKNAS neuroblastoma cells with inducible N-MYC-ER, Replicate #2 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites, is disrupted across many human cancers. Deregulated expression of MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC suppresses oscillation of gene expression and metabolism to instead upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC or the closely related N-MYC were examined, using detailed time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression, programs, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter proteins while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.
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| Overall design |
We activated SKNAS N-MYC-ER in cells for 24 hours with 4-hydroxytamoxifen (4OHT, MYC-ON), or used vehicle control (MYC-OFF). We then entrained cells circadian rhythms with dexamethasone. 24 hours after dexamethasone treatment, cells were then collected every 4 hours for up to 48 hours, and RNA was extracted. CT refers to circadian time, ie, hours after dexamethasone entrainment. RNA at approximately 66.67 ng/µL was submitted to the University of Rochester Genomics Research Center (GRC) was analyzed by TapeStation and determined to have an average RNA Integrity Number (RIN) of 9.3. RNA-sequencing was performed on polyadenylated mRNAs using an Illumina NovaSeq 6000 as 100 base paired end sequencing,, yielding an average of 93.1 million reads per sample (when adding together both paired ends). Reads were mapped with Salmon, and collapsed to gene level with Tximport. This experiment is a biological replicate to the SKNAS time series in GSE221103.
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| Web link |
https://pubmed.ncbi.nlm.nih.gov/37639465/
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| Contributor(s) |
Altman BJ, Dang CV |
| Citation(s) |
37639465 |
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| Submission date |
Jul 18, 2023 |
| Last update date |
Oct 17, 2023 |
| Contact name |
Brian James Altman |
| E-mail(s) |
brian_altman@urmc.rochester.edu
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| Phone |
5852765877
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| Organization name |
University of Rochester
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| Department |
Biomedical Genetics
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| Street address |
601 Elmwood Avenue Box 633
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| City |
Rochester |
| State/province |
NY |
| ZIP/Postal code |
14620 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (26)
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| GSM7634748 |
SKNAS N-MYC-ER MYC-OFF CT24 Replicate 2 |
| GSM7634749 |
SKNAS N-MYC-ER MYC-OFF CT28 Replicate 2 |
| GSM7634750 |
SKNAS N-MYC-ER MYC-OFF CT32 Replicate 2 |
| GSM7634751 |
SKNAS N-MYC-ER MYC-OFF CT36 Replicate 2 |
| GSM7634752 |
SKNAS N-MYC-ER MYC-OFF CT40 Replicate 2 |
| GSM7634753 |
SKNAS N-MYC-ER MYC-OFF CT44 Replicate 2 |
| GSM7634754 |
SKNAS N-MYC-ER MYC-OFF CT48 Replicate 2 |
| GSM7634755 |
SKNAS N-MYC-ER MYC-OFF CT52 Replicate 2 |
| GSM7634756 |
SKNAS N-MYC-ER MYC-OFF CT56 Replicate 2 |
| GSM7634757 |
SKNAS N-MYC-ER MYC-OFF CT60 Replicate 2 |
| GSM7634758 |
SKNAS N-MYC-ER MYC-OFF CT64 Replicate 2 |
| GSM7634759 |
SKNAS N-MYC-ER MYC-OFF CT68 Replicate 2 |
| GSM7634760 |
SKNAS N-MYC-ER MYC-OFF CT72 Replicate 2 |
| GSM7634761 |
SKNAS N-MYC-ER MYC-ON CT24 Replicate 2 |
| GSM7634762 |
SKNAS N-MYC-ER MYC-ON CT28 Replicate 2 |
| GSM7634763 |
SKNAS N-MYC-ER MYC-ON CT32 Replicate 2 |
| GSM7634764 |
SKNAS N-MYC-ER MYC-ON CT36 Replicate 2 |
| GSM7634765 |
SKNAS N-MYC-ER MYC-ON CT40 Replicate 2 |
| GSM7634766 |
SKNAS N-MYC-ER MYC-ON CT44 Replicate 2 |
| GSM7634767 |
SKNAS N-MYC-ER MYC-ON CT48 Replicate 2 |
| GSM7634768 |
SKNAS N-MYC-ER MYC-ON CT52 Replicate 2 |
| GSM7634769 |
SKNAS N-MYC-ER MYC-ON CT56 Replicate 2 |
| GSM7634770 |
SKNAS N-MYC-ER MYC-ON CT60 Replicate 2 |
| GSM7634771 |
SKNAS N-MYC-ER MYC-ON CT64 Replicate 2 |
| GSM7634772 |
SKNAS N-MYC-ER MYC-ON CT68 Replicate 2 |
| GSM7634773 |
SKNAS N-MYC-ER MYC-ON CT72 Replicate 2 |
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| This SubSeries is part of SuperSeries: |
| GSE221174 |
MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis |
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| Relations |
| BioProject |
PRJNA996029 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE237608_SKNAS_Replicate2_Timecourse_TPM.txt.gz |
3.5 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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