Transcriptional kinases drive gene expression network plasticity.

Eukaryotic transcription is a highly dynamic and adaptable process that underpins the gene expression programs regulating development, cellular identity, and responses to extracellular signals. Gene-specific regulation of transcription across different cell types and environmental conditions is therefore fundamental to both normal physiology and disease. This specificity is shaped by phosphorylation of the RNA polymerase II (RNAPII) C-terminal domain (CTD) and its associated transcription factors. While cyclin-dependent kinases (CDKs) have long been recognized as the regulators of RNAPII activity, emerging evidence points to a broader, more diverse network of transcriptional kinases. Here, we highlight non-canonical transcriptional kinases that could operate alongside and beyond CDKs to modulate transcription by RNAPII. We discuss how these kinases could introduce context-specific CTD modifications that enable transcriptional plasticity, facilitate rapid loci-specific activation, and integrate signaling and stress-responsive pathways, ultimately adding a layer of regulatory complexity with profound implications for dynamic transcriptional regulation in development, homeostasis, and disease.