You are here:
Evaluating biological activity of compounds by transcription factor activity profiling
Citation:
Medvedev, A., M. Moeser, L. Medvedeva, E. Martsen, A. Granick, L. Raines, M. Zeng, S. Makarov Jr., K. Houck, AND S. Makarov. Evaluating biological activity of compounds by transcription factor activity profiling. Science Advances. American Association for the Advancement of Science (AAAS), Washington, DC, 4(9):eaar4666, (2018).
Impact/Purpose:
Manuscript describing use of transcription factor activation assay to assess effects of chemicals on human liver cell line.
Description:
A main objective of biomedical research is evaluation of biological activity of compounds. Here, we show that compounds’ bioactivity can be inferred by assessing responses of transcription factors, cellular proteins that modulate gene expression. Using a multiplex reporter system, the FACTORIAL™, we characterized cell response by transcription factor activity profile (TFAP), a quantitative signature reflecting changes of multiple TFs’ activity. We found that perturbing biological pathways in human cells elicited distinct TFAPs. Remarkably, perturbagens of the same pathway produced an invariant TFAP, regardless of where or how the pathway was disrupted. We found invariant TFAPs for mitochondrial, HDAC, and ubiquitin/proteasome pathway inhibitors; cytoskeleton disruptors; and DNA-damaging agents, and show that these signatures permitted identifying compounds with intended activities among uncharacterized chemicals. Furthermore, we show that TFAPs of polypharmacological drugs can reveal their multiple bioactivities. Thus, TF activity profiling affords straightforward assessment of compounds’ bioactivity through identification of perturbed biological pathways.
