A gene expression biomarker identifies inhibitors of two classes of epigenome effectors in a human microarray compendium. (25th September 2022)

• Record Type: Journal Article
• Authors: Corton, J. Christopher; Liu, Jie; Williams, Andrew; Cho, Eunnara; Yauk, Carole L.
• Is Part Of: Chemico-biological interactions. Volume 365(2022)
• Publication Date: 2022-09-25
• Subjects: histone Deacetylase inhibitor -- Gene expression profiling -- Biomarker -- Toxicogenomics -- Bromodomain and extraterminal (BET) family -- High throughput transcript profiling; AOPs adverse outcome pathways -- BET bromodomain and extraterminal -- BRD bromodomain -- BSCE BaseSpace Correlation Engine -- CMAP Connectivity Map -- EPA Environmental Protection Agency -- HDAC histone deacetylase -- HTTr High-throughput transcriptomic -- KEs key events -- MIEs molecular initiating events -- PTM protein modification; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2022.110032
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Biomarkers predictive of molecular and toxicological effects are needed to interpret emerging high-throughput transcriptomics (HTTr) data streams. To address the limited approaches available for identifying epigenotoxicants, we previously developed and validated an 81-gene biomarker that accurately predicts histone deacetylase inhibition (HDACi) in transcript profiles derived from chemically-treated TK6 cells. In the present study, we sought to determine if this biomarker (TGx-HDACi) could be used to identify HDACi chemicals in other cell lines using the Running Fisher correlation test. Using microarray comparisons derived from human cells exposed to HDACi, we found considerable heterogeneity in correlation with the TGx-HDACi biomarker dependent on chemical exposure conditions and tissue from which the cell line was derived. Using a defined set of conditions that overlapped with our earlier study, the biomarker was able to accurately identify HDACi chemicals (90–100% balanced accuracy). In an in silico screen of 2427 chemicals in 9660 chemical versus control comparisons, the biomarker coupled with the Running Fisher test was able to identify 14 additional HDACi chemicals as well as other chemicals not previously associated with HDACi. Most notable were 12 inhibitors of bromodomain (BRD) and extraterminal (BET) family proteins including BRD4 that bind to acetylated histones. The BET protein inhibitors could be distinguished from the HDACi based on differences in the expression of a small set of biomarker genes. Our results indicate that the TGx-HDACi biomarker will be useful for identifying inhibitors of two classes of epigenome effectors in HTTr screening studies. Graphical abstract: Image 1 Highlights: Gene expression biomarkers can predict effects in gene expression data. Limited approaches for identifying epigenotoxicants including HDAC inhibitors. A biomarker (TGx-HDACi) has been used to identify HDACi chemicals in TK6 cells. TGx-HDACi identified HDACi chemicals in other cell lines. TGx-HDACi identified inhibitors of BET proteins that bind to acetylated histones.