Chemical-genetics refines transcription factor regulatory circuits

Abstract

Transcriptional dysregulation is a key step in oncogenesis, but our understanding of transcriptional control has relied on genetic approaches that are slow and allow for compensation. Chemical-genetic approaches have shortened the time frame for the analysis of transcription factors from days or weeks to minutes. These studies show that while DNA-binding proteins bind to thousands of sites, they are directly required to regulate only a small cadre of genes. Moreover, these transcriptional control networks are far more distinct, with much less overlap and interconnectivity than predicted from DNA binding. The identified direct targets can then be used to dissect the mechanism of action of these factors, which could identify ways to therapeutically manipulate these oncogenic transcriptional control networks.

Keywords: PROTACs; cancer; chemical-genetics; degron tags; molecular glue; therapeutics; transcription.

Figure 1.

Key figure. Chemical-genetics enable the temporal analysis of transcription. Traditional methods of genetic perturbation (knockout or RNAi knockdown) require days to weeks to establish stable models of transcriptional dysregulation. Genomic analysis of these models does not allow the separation of the primary response to the disruption of a transcriptional regulator from the secondary and tertiary responses that occur after the fact. Chemical-genetic perturbation of transcriptional regulators can disrupt protein function in just minutes. The combination of chemical genetics with nascent RNA analysis can help delineate the primary and secondary responses to perturbation of transcriptional regulators. (Adapted with permission from Swift and Corruzzi [86]).