Transcriptomics hit the target: Monitoring of ligand-activated and stress response pathways for chemical testing

Area of Science:

• Toxicology
• Molecular Biology
• Genomics

Background:

• High-content omics methods offer deep cellular insights but lack mechanistic understanding for interpreting biological changes.
• Transcriptomics (TCX) can reveal transcription factor (TF) activity modulation, a key molecular effect of chemical exposure.
• Publicly available ChIP-seq data enables the creation of TF target gene lists for toxicological relevance.

Purpose of the Study:

• To generate target gene signatures for key transcription factors (Nrf2, ATF4, XBP1, p53, HIF1a, AhR, PPAR gamma).
• To track TF modulation in a large dataset of in vitro transcriptomics data from renal and hepatic cell models.
• To establish a mechanistically based tool for chemical hazard identification.

Main Methods:

• Generation of TF target gene signatures using ChIP-seq data.
• Analysis of in vitro transcriptomics (TCX) datasets from renal and hepatic cell models.
• Exposure of cell models to clinical nephro- and hepato-toxins.

Main Results:

• Successfully generated target gene signatures for seven key transcription factors.
• Tracked TF modulation across a comprehensive collection of in vitro TCX datasets.
• Demonstrated the potential for global monitoring of TF modulation in response to chemical exposure.

Conclusions:

• The developed TF target gene signatures provide a mechanistically based approach to interpret transcriptomic changes.
• Global monitoring of TF modulation shows promise as a tool for chemical hazard identification.
• This approach enhances the interpretation of high-content omics data in toxicology.