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Development And Validation Of A Transcriptomic Biomarker Of Chemical-Induced Histone Deacetylase Inhibition In TK6 Cells
Citation:
Cho, E., A. Rowan-Carroll, A. Williams, C. Corton, H. Li, A. Fornace, C. Hobbs, AND C. Yauk. Development And Validation Of A Transcriptomic Biomarker Of Chemical-Induced Histone Deacetylase Inhibition In TK6 Cells. 2020 Environmental Mutagenesis and Genomics Society, Palm Springs, CA, September 12 - 16, 2020. https://doi.org/10.23645/epacomptox.26014903
Impact/Purpose:
Histone deacetylase inhibitors (HDACi) are epigenotoxicants that disrupt gene expression by modulating histone acetylation. We developed a transcriptomic biomarker of HDACi in human TK6 cells to address the limitations in tools available for identifying HDACi in chemical screening.
Description:
Histone deacetylase inhibitors (HDACi) are epigenotoxicants that disrupt gene expression by modulating histone acetylation. We developed a transcriptomic biomarker of HDACi in human TK6 cells to address the limitations in tools available for identifying HDACi in chemical screening. First, we selected 10 HDACi and 10 non-HDACi compounds to represent each class. One concentration of each compound was selected for biomarker derivation based on gene expression and viability after 4 hr exposures in range finding experiments. The selected concentrations induced the highest response in three indicator genes (RGL1, NEU1, and GPR183; selected from a survey of public data) after 4 hrs, without >50% cytotoxicity at 24 hrs. HDAC enzyme activity assay confirmed all reference compounds to be HDACi or non-HDACi at the selected concentrations. Whole transcriptomes were profiled in cells exposed to each reference compound for 4hrs by TempO-seq. A nearest shrunken centroid (NSC) method was applied to the gene expression profiles to identify a panel of genes whose expression pattern can accurately classify all 20 reference compounds by their respective classes in a probability analysis. To evaluate the classification capability, an additional four HDACi and seven non-HDACi compounds were profiled and classified using the same methods. The biomarker classified all 11 chemicals correctly, demonstrating 100% accuracy. Furthermore, in a correlation analysis using the Running Fisher test, the biomarker demonstrated strong positive correlations to HDACi gene expression profiles generated in cell lines other than TK6, suggesting a broader applicability. This biomarker can be used in transcriptomic screening to identify potential HDACi. (This abstract does not represent EPA policy.)
URLs/Downloads:
DOI: Development And Validation Of A Transcriptomic Biomarker Of Chemical-Induced Histone Deacetylase Inhibition In TK6 Cells
EMGS 2020 POSTER_HDACI SIGNATURE_STICS.PDF (PDF, NA pp, 1047.961 KB, about PDF)