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A gene expression biomarker identifies inhibitors of two classes of epigenome effectors in a human microarray

J Christopher Corton1, Jie Liu1, Andrew Williams2

  • 1Center for Computational Toxicology and Exposure, US Environmental Protection Agency, Research Triangle Park, NC, 27711, USA.

Chemico-Biological Interactions
|July 1, 2022
PubMed

Insights

A new biomarker accurately identifies histone deacetylase inhibitors (HDACi) in high-throughput transcriptomics data. This epigenetics biomarker also detects bromodomain and extraterminal (BET) protein inhibitors, expanding its utility in toxicological screening.

Area of Science:

  • Toxicogenomics
  • Epigenetics
  • Biomarker Development

Background:

  • High-throughput transcriptomics (HTTr) data requires robust biomarkers for interpreting molecular and toxicological effects.
  • Identifying epigenotoxicants is challenging due to limited available approaches.
  • An 81-gene biomarker (TGx-HDACi) was previously developed to predict histone deacetylase inhibition (HDACi) in TK6 cells.

Purpose of the Study:

  • To evaluate the TGx-HDACi biomarker's ability to identify HDACi chemicals in diverse cell lines using the Running Fisher correlation test.
  • To assess the biomarker's performance across different chemical exposure conditions and cell line origins.
  • To screen a large chemical library for novel HDACi and other epigenome-modulating compounds.

Main Methods:

  • Application of the TGx-HDACi biomarker and Running Fisher correlation test to microarray data from human cells exposed to HDACi.
  • Validation of biomarker performance under defined conditions overlapping with previous studies.
  • In silico screening of 2427 chemicals against 9660 chemical versus control comparisons.

Main Results:

  • Considerable heterogeneity was observed in biomarker correlation based on cell line and exposure conditions.
  • Under defined conditions, the biomarker accurately identified HDACi chemicals with 90-100% balanced accuracy.
  • The screen identified 14 additional HDACi chemicals and 12 bromodomain and extraterminal (BET) protein inhibitors, including BRD4 inhibitors.
  • BET protein inhibitors were distinguishable from HDACi by specific biomarker gene expression patterns.

Conclusions:

  • The TGx-HDACi biomarker is effective for identifying HDACi across different cell lines, though performance varies with conditions.
  • The biomarker successfully identified novel HDACi and BET protein inhibitors in a large-scale in silico screen.
  • TGx-HDACi is a valuable tool for identifying inhibitors of both HDAC and BET epigenetic effector classes in HTTr screening studies.
Keywords:
BiomarkerBromodomain and extraterminal (BET) familyGene expression profilingHigh throughput transcript profilingToxicogenomicshistone Deacetylase inhibitor

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