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Transcriptomic analysis of sturgeon embryos in response to chemically induced DNA damage

ABSTRACT: In this study we show that the exposure to genotoxicants (10 nM camptothecin and 20 µM Olaparib) affects embryo development in a stage-dependent manner with early stages being the most sensitive to DNA damage. The transcriptomic and proteomic patterns changed significantly after exposure to genotoxicants compared to the control. Camptothecin and Olaparib downregulated metabolic pathways and developmental processes. Additionally, the exposure to genotoxicants led to upregulation of cell proliferation, neural precursor cell proliferation, generation of neurons, taxis and locomotion. Protein patterns were altered as well by DNA damage. The results of this study indicate that there is a strong correlation between phenotype formation and changes in transcriptomic and proteomic profiles.

ORGANISM(S): Acipenser ruthenus

PROVIDER: GSE190524 | GEO | 2022/06/29

REPOSITORIES: GEO

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Project description:MYC-driven Group 3 medulloblastoma (MB) (subtype II) is a highly aggressive childhood brain tumor. Sensitivity of MYC-driven MBs to class I histone deacetylase inhibitors (HDACi) has been previously demonstrated in vitro and in vivo. We here characterize the transcriptional effects of class I HDAC inhibition in MYC-driven MB and explore beneficial drug combinations. MYC-amplified Group 3 MB cells (HD-MB03) were treated with class I HDACi entinostat. Changes in the gene expression profile compared to untreated control were quantified on a microarray. Gene set enrichment analysis, cytoscape enrichment mapping and ingenuity pathway analysis led to the identification of pathways affected by entinostat treatment. Five drugs interfering with these pathways (olaparib, idasanutlin, ribociclib, selinexor, vinblastine) were tested as single agents in metabolic activity assays in three MYC-amplified and two non-MYC-amplified MB cell lines. Synergy with entinostat was evaluated by dose response curve shift, combination index and zero interaction potency synergy model and validated in cell count and flow cytometry experiments in two MYC-amplified and one non-MYC-amplified MB cell line. The effect of the most promising drug combination (entinostat and olaparib) on DNA damage was evaluated by γH2A.X quantification in immunoblotting, fluorescence microscopy and flow cytometry. Entinostat treatment changed the expression of genes involved in 22 pathways, including downregulation of DNA damage response. The PARP1 inhibitors olaparib and pamiparib showed synergy with entinostat. The combination of entinostat and olaparib led to increased cell death, decreased viability and increased formation of double strand breaks selectively in MYC-amplified MB cells. MYC-amplified MB cells treated with entinostat and olaparib were particularly vulnerable to additional induction of DNA damage by doxorubicin. Non-MYC-amplified MB cells and normal human fibroblasts were not susceptible to this triple treatment. Our study identifies the combination of entinostat with olaparib and doxorubicin as a new potential therapeutic approach for MYC-driven Group 3 MB.

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Transcriptomic analysis of sturgeon embryos in response to chemically induced DNA damage

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